Tricyclic Indeno-Pyrrole Derivatives as Serotonin Receptor Modulators

ABSTRACT

The present invention generally relates to a series of compounds, to pharmaceutical compositions containing the compounds, and to use of the compounds and compositions as therapeutic agents. More specifically, compounds of the present invention are tricyclic indeno-pyrrole compounds. These compounds are serotonin receptor (5-HT) ligands and are useful for treating diseases, disorders, and conditions wherein modulation of the activity of serotonin receptors (5-HT) is desired (e.g. anxiety, depression and obesity).

This application is a continuation of U.S. patent application Ser. No. 12/478,362, filed on Jun. 4, 2009, which is a continuation of U.S. patent application Ser. No. 11/189,952, filed on Jul. 26, 2005 and which claims a priority of U.S. Provisional Patent Application Ser. No. 60/592,047, filed on Jul. 29, 2004.

FIELD OF THE INVENTION

The present invention generally relates to a series of compounds, to pharmaceutical compositions containing the compounds, and to use of the compounds and compositions as therapeutic agents. More specifically, compounds of the present invention are tricyclic indeno-pyrrole compounds. These compounds are serotonin receptor (5-HT) ligands and are useful for treating diseases, disorders, and conditions wherein modulation of the activity of serotonin receptors (5-HT) is desired (e.g. addiction, anxiety, depression and obesity).

BACKGROUND OF THE INVENTION

Serotonin has been implicated in a number of diseases, disorders, and conditions that originate in the central nervous system, including diseases, disorders, and conditions related to, for example, sleeping, eating, perceiving pain, controlling body temperature, controlling blood pressure, depression, anxiety, addiction and schizophrenia. Serotonin also plays an important role in peripheral systems, such as the gastrointestinal system, where it has been found to mediate a variety of contractile, secretory, and electrophysiologic effects.

Because of the broad distribution of serotonin within the body, there is a need for drugs that affect serotonergic systems. In particular, agonists, partial agonists, and antagonists of serotonergic systems are of interest for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, obesity, compulsive disorders, schizophrenia, autism, neurodegenerative disorders (e.g., Alzheimer's disease, Parkinsonism, and Huntington's chorea), and chemotherapy-induced vomiting.

The major classes of serotonin receptors (5-HT₁₋₇) contain one to seven separate receptors that have been formally classified. See Glennon, et al., Neuroscience and Behavioral Reviews, 1990, 14, 35; and D. Hoyer, et al. Phannacol. Rev. 1994, 46, 157-203.

For example, the 5-HT₂ family of receptors contains 5-HT_(2a), 5-HT_(2b), and 5-HT_(2c) subtypes, which have been grouped together on the basis of primary structure, secondary messenger system, and operational profile. All three 5-HT₂ subtypes are G-protein coupled, activate phospholipase C as a principal transduction mechanism, and contain a seven-transmembrane domain structure. There are distinct differences in the distribution of the three 5-HT₂ subtypes in a mammal. The 5-HT_(2b) and 5-HT_(2a) receptors are widely distributed in the peripheral nervous system, with 5-HT_(2a) also found in the brain. The 5-HT_(2c) receptor has been found only in the central nervous system, being highly expressed in many regions of the human brain. See G. Baxter, et al. Trends in Pharmacol. Sci. 1995, 16, 105-110.

Subtype 5-HT_(2a) has been associated with effects including vasoconstriction, platelet aggregation, and bronchoconstriction, as well as certain CNS effects, while subtype 5-HT₂, has been associated with diseases that include depression, anxiety, obsessive compulsive disorder, addiction, panic disorders, phobias, psychiatric syndromes, and obesity. Very little is known about the pharmocologic role of the 5-HT_(2b) receptor. See F. Jenck, et al., Exp. Opin. Invest. Drugs, 1998, 7, 1587-1599; M. Bos, et al., J. Med. Chem., 1997, 40, 2762-2769; J. R. Martin, et al., The Journal of Pharmacology and Experimental Therapeutics, 1998, 286, 913-924; S. M. Bromidge, et al., 1. Med. Chem., 1998, 41, 1598-1612; G. A. Kennett, Drugs, 1998, 1, 4, 456-470; and A. Dekeyne, et al., Neurophannacology, 1999, 38, 415-423.

U.S. Pat. Nos. 4,622,405; 5,049,564 and 5,244,888 and WO 90/06927 disclose various indeno-pyrrole derivatives.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of the formula:

where

R₁ is selected from the group consisting of H, halogen, C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, perhaloalkyl, CN, N(R₆)₂, SR₆, CON(R₆)₂, NR₆COR₇, NR₆CO₂R₇, SO₂N(R₆)₂, NR₆SO₂R7, aryl, heteroaryl, C₁₋₁₀alkylaryl, and C₁₋₁₀alkylheteroaryl;

R₂, R₃ and R₄ are independently selected from the group consisting of H, halogen, C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, perhaloalkyl, CN, OR₆, N(R₆)₂, SR₆, OCOR₇, CON(R₆)₂, NR₆COR₇, NR₆CO₂R₇, SO₂N(R₆)₂, NR₆SO₂R₇, aryl, heteroaryl, C₁₋₁₀ alkylaryl, and C₁₋₁₀alkylheteroaryl or R₂ and R₃ together with the ring to which they are attached form a 5 to 7 membered carbocylic or heterocyclic ring;

R₅ is selected from the group consisting of H, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, perhaloalkyl, CN, OR₆, N(R₆)₂, SR₆, OCOR₇, CON(R₆)₂, NR₆COR₇, NR₆CO₂R₇, NR₆SO₂R₇, aryl, heteroaryl, C₁₋₁₀alkylaryl, and C₁₋₁₀ alkylheteroaryl, or R₄ and R₅ together with the ring to which they are attached form a 6 to 8 membered aryl or heteroaryl ring;

R_(5a) is H; or R₅ and R_(5a) taken together form a cyclopropane ring;

R₆ is selected from the group consisting of H, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, perhaloalkyl, C₁₋₁₀ alkyl-O—C₁₋₁₀ alkyl, aryl, heteroaryl, C₁₋₁₀alkyl-0-aryl, C₁₋₁₀ alkyl-O-heteroaryl, C₁₋₁₀ alkylaryl, and C₁₋₁₀ alkylheteroaryl; and

R₇ is selected from the group consisting of C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, perhaloalkyl, C₁₋₁₀alkyl-O—C₁₋₁₀ alkyl, aryl, heteroaryl, C₁₋₁₀alkyl-O-aryl, C₁₋₁₀alkyl-O-aryl, C₁₋₁₀alkyl-O-heteroaryl, C₁₋₁₀ alkylaryl, and C₁₋₁₀ alkylheteroaryl;

provided that if R₁, R₂, R₅ and R_(5a) are H, then R₃ and/or R₄ must be H and the pharmaceutically acceptable salts thereof.

Included herein are the various stereoisomers of the compounds of Formula (I).

Another embodiment of the present invention provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Still another embodiment of the present invention provides a method of treating a disease, disorder and/or condition in a mammal (e.g., animal or human), wherein a 5-HT_(2c) receptor is implicated and modulation of a 5-HT_(2c) function is desired. The method comprises administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the mammal.

Yet another embodiment of the present invention comprises a method of modulating 5-HT receptor function with an effective amount of compound of Formula (I), or a pharmaceutically acceptable salt thereof.

A further embodiment of the present invention provides a method of treating or preventing diseases, disorders, and/or conditions of the central nervous system. The method comprises administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the mammal.

Specific diseases, disorders and/or conditions for which compounds of the Formula (I) may have activity include cardiovascular disorders, obesity, depression, schizophrenia, anxiety, obsessive compulsive disorder, addiction, panic disorders, sleep disorders, migraine, Type II diabetes, epilepsy, phobias and psychiatric syndromes.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions are used, unless otherwise described:

As used herein, the term “alkyl” includes straight chained and branched hydrocarbon groups containing the indicated number of carbon atoms, typically methyl, ethyl, and straight chain and branched propyl and butyl groups. The term “alkyl” also encompasses cycloalkyl, i.e., a cyclic C₃-C₈ hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Reference to an individual group or moiety, such as “propyl,” embraces only the straight chain group or moiety. A branched chain isomer, such as “isopropyl,” is specifically referred to.

The term “alkenyl” as used herein, alone or in combination, refers to a substituted or unsubstituted straight-chain or substituted or unsubstituted branched-chain alkenyl radical containing from 2 to 10 carbon atoms. Examples of such radicals include, but are not limited to, ethenyl, E- and Z-pentenyl, decenyl and the like.

The term “alkynyl” as used herein, alone or in combination, refers to a substituted or unsubstituted straight or substituted or unsubstituted branched chain alkynyl radical containing from 2 to 10 carbon atoms. Examples of such radicals include, but are not limited to, ethynyl, propynyl, propargyl, butynyl, hexynyl, decynyl and the like.

The term “alkoxy” as used herein, alone or in combination, refers to an alkyl ether radical, wherein the term “alkyl” is as defined above. Examples of suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.

The term “halo” is defined herein to include fluoro, chloro, bromo, or iodo. Similarly, the term “halogen” is defined herein to include fluorine, chlorine, bromine, and iodine.

The term “amino”, alone or in combination, includes the group —NH₂ or —NR_(a)R_(b) wherein R_(a) and R_(b) are independently hydrogen, alkyl or aryl.

The term “aryl,” alone or in combination, is defined herein as a monocyclic or bicyclic aromatic group (e.g., phenyl or naphthyl) that can be unsubstituted or substituted, for example, with one or more, and in particular one to three of the following substituents selected from the group consisting of H, halo, CN, NO₂, CF₃, N₃, C₁₋₆ alkyl, OH, NR^(a)R^(b), OC₁₋₆ alkyl, OR^(a), C(═O)NR^(a)R^(b), C(═S)NR^(a)R^(b), tetrazoyl, triazoyl, amidinyl, guanidinyl, thioguanidinyl, cyanoguanadinyl, and aryl. Generally, “aryl” denotes a phenyl group, or an ortho-fused bicyclic carbocyclic group having nine to ten ring atoms in which at least one ring is aromatic (e.g. naphthyl or tetrahydronaphthyl). The term “aryl” also is abbreviated in the various chemical structures as “Ar.”

The term “carbocylic” includes any closed ring of carbon atoms, including alicyclic and aromatic structures.

The term “heteroaryl” is defined herein as a monocyclic, bicyclic, or tricyclic ring system containing one, two, or three aromatic rings and containing at least one nitrogen, oxygen, or sulfur atom in an aromatic ring, and which can be unsubstituted or substituted, for example, with one or more, and in particular one to three, substituents, like halo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkyl, nitro, amino, alkylamino, acylamino, alkylthio, alkylsulfonyl, and alkylsulfonyl. Examples of heteroaryl groups include, but are not limited to, 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, 4H-carbazolyl, acridinyl, benzo[b]thienyl, benzothiazolyl, 1,3-carbolinyl, carbazolyl, chromenyl, cinnaolinyl, dibenzo[b,d]furanyl, furazanyl, furyl, imidazolyl, imidizolyl, indazolyl, indolisinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, naptho[2,3-b], oxazolyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl, triazolyl, and xanthenyl. In one embodiment the term “heteroaryl” denotes a monocyclic aromatic ring containing five or six ring atoms containing carbon and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of non-peroxide oxygen, sulfur, and N(Z) wherein Z is absent or is H, O, C₁₋₄alkyl, phenyl or benzyl. In another embodiment heteroaryl denotes an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, or tetramethylene diradical thereto.

The term “Het” generally represents a heterocyclic group, saturated or partially unsaturated, containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur, and optionally substituted with C₁₋₆alkyl or C(═O)OR^(b). Typically “Het” is a monocyclic, bicyclic, or tricyclic group containing one or more heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. A “Het” group also can contain an oxo group (=0) attached to the ring. Nonlimiting examples of Het groups include 1,3-dihydrobenzofuran, 1,3-dioxolane, 1,4-dioxane, 1,4-dithiane, furanyl, imidazolyl, 2H-pyran, 2-pyrazoline, 4H-pyran, chromanyl, imidazolidinyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl, morpholine, oxazolyl, piperazinyl, piperidine, piperidynyl, pyrazolidine, pyrimidinyl, pyrazolidinyl, pyrazolinyl, pyrrolidine, pyrroline, quinuclidine, and thiomorpholine.

Preferably, R₁ is C₁₋₅ alkyl, halogen, CF₃, aryl, heteroaryl or H; R₂,R₃ and R₄ are independently C₁₋₅alkyl, —O—R₆, halogen, CF₃, aryl, heteroaryl or H; R₅ is C₁₋₆-alkyl, —OR₆ or C₂₋₆alkene; and R₆ is C₁₋₆alkyl or H.

Presently preferred compounds include:

-   5-Methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole; -   5-Hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole; -   5-Methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole; -   5-Hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole; -   6-Chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole; -   5-(4-Flourobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole; -   5-Benzyloxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole; -   5-(2-Fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole; -   5-(3-Fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole; -   1,2,3,3a,8,8a-Hexahydroindeno[1,2-c]pyrrole; -   6-Chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole; -   6,7-Dichloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole; -   4,5-Dimethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole; -   4,6-Dichloro-5-Methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;     and -   6-(2,6-Difluorophenyl)-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.

Certain compounds of the invention may exist in different isomeric (e.g. enantiomers and distereoisomers) forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Enol forms are also included.

The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., hemi-hydrate. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol, and the like are equivalent to the unsolvated forms for the purposes of the invention.

Certain compounds of the invention also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, the nitrogen atoms may form salts with acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, furmaric, succinic, ascorbic, maleic, methanesulfonic and other mineral carboxylic acids well known to those in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous hydroxide potassium carbonate, ammonia, and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid salts are equivalent to their respective free base forms for purposes of the invention. (See, for example S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 66: 1-19 (1977) which is incorporated herein by reference.

As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from a combination of the specified ingredients in the specified amounts.

The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The phrase “pharmaceutically acceptable salt” means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1 et seq. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.

Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, and ethylammonium among others. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.

Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which can be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention can be varied so as to obtain an amount of the active compound(s) which is effective to achieve the desired therapeutic response for a particular patient, compositions and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

When used in the above or other treatments, a therapeutically effective amount of one of the compounds of the present invention can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester or prodrug form. Alternatively, the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable excipients. The phrase “therapeutically effective amount” of the compound of the invention means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

The total daily dose of the compounds of this invention administered to a human or lower animal may range from about 0.0001 to about 1000 mg/kg/day. For purposes of oral administration, more preferable doses can be in the range of from about 0.001 to about 5 mg/kg/day. If desired, the effective daily dose can be divided into multiple doses for purposes of administration; consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.

The present invention also provides pharmaceutical compositions that comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions can be specially formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.

The pharmaceutical compositions of this invention can be administered to humans and other mammals orally, rectally, parenterally , intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray. The term “parenterally,” as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

In another aspect, the present invention provides a pharmaceutical composition comprising a component of the present invention and a physiologically tolerable diluent. The present invention includes one or more compounds as described above formulated into compositions together with one or more non-toxic physiologically tolerable or acceptable diluents, carriers, adjuvants or vehicles that are collectively referred to herein as diluents, for parenteral injection, for intranasal delivery, for oral administration in solid or liquid form, for rectal or topical administration, among others.

The compositions can also be delivered through a catheter for local delivery at a target site, via an intracoronary stent (a tubular device composed of a fine wire mesh), or via a biodegradable polymer. The compounds may also be complexed to ligands, such as antibodies, for targeted delivery.

Compositions suitable for parenteral injection may comprise physiologically acceptable, sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), vegetable oils (such as olive oil), injectable organic esters such as ethyl oleate, and suitable mixtures thereof.

These compositions can also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.

In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include⁻pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfumingagents.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like. The preferred lipids are natural and synthetic phospholipids and phosphatidyl cholines (lecithins) used separately or together.

Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.

The term “pharmaceutically acceptable prodrugs” as used herein represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. Prodrugs of the present invention may be rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987), hereby incorporated by reference.

The compounds of the present invention may be prepared by the procedures set forth in Schemes 1, 2 and 3. The general analytical conditions set forth after the Schemes were utilized in all examples.

General Analytical Conditions:

HPLC analysis and purification was performed using a Waters 2525 binary gradient pump, Waters 2767 sample manager, waters 2487 UV detector (220 and 254 nM), and Waters Micromass ZQ electrospray mass spec detector. The Micromass ZQ was set for both positive and negative ionization (cone voltage=25 and 50, respectively).

Analytical HPLC analysis was performed as follows:

Waters XTerra MS C18 50×4.6 mm 3.5 μm column

Mobile Phase: 10 mM Ammonium Acetate buffer at pH 5.75 and Acetonitrile

Acetonitrile: 10 to 75% at 3.5 minutes, 75 to 99% at 3.9 minutes, 99% hold to 4.2 minutes, 99 to 10% at 4.5 minutes, re-equilibrate.

Preparative HPLC was performed as follows:

Waters XTerra Prep MS C18 50×19 mm 5 μm column

Mobile Phase: 10 mM Ammonium Acetate buffer at pH 5.75 and Acetonitrile

Acetonitrile: 10 to 99% at 8 minutes, 99% hold to 9 minutes, 99 to 10% at 9.5 minutes, re-equilibrate

NMR analysis was performed using a Bruker BioSpin UltraShield NMR (300 MHz)

EXAMPLES Example 1 5-Methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-Bromo-5-methoxy-1-indanone. (Scheme 1)

N-bromosuccinimide (12.1 g, 67.9 mmol) and 2,2′-azobisisobutyronitrile (0.1 g, 0.6 mmol) were added to a solution of 5-methoxy-1-indanone (10.0 g, 61.7 mmol) in carbon tetrachloride (104 mL). The reaction mixture was stirred for 3 hours at 85° C. and then allowed to cool to room temperature. The reaction mixture was filtered through Celite, which was then washed with CH₂Cl₂ (100 mL). The filtrate was washed with brine (50 mL), dried over MgSO₄, and concentrated to afford the subtitle compound, which was used without further purification. MS calculated for C₁₀H₉BrO₂+H: 241, observed: 241.

Step B. 5-Methoxy-inden-1-one

DBU (9.2 mL, 61.7 mmol) was added to a solution of 5-methoxy-3-bromo-1-indanone (14.8 g, 61.7 mmol) in THF (100 mL) at −10° C. dropwise over 10 minutes. The resulting solution was stirred at −10° C. for 20 minutes, quenched via addition of saturated aqueous NH₄Cl (100 mL), and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO₄, and concentrated. The crude product was purified by column chromatography (SiO₂) using a 0-35% ethyl acetate-hexanes gradient to afford 5.4 g (55%—two steps) of the subtitle compound. ¹H NMR (CDCl₃ 300 MHz) δ 7.42 (d, 1H), 7.38 (d, 1H), 6.62 (s, 1H), 6.60 (d, 1H), 5.89 (d, 1H), 3.85 (s, 3H) ppm. MS calculated for C₁₀H₈O₂+H: 161, observed: 161.

Step C. 2-Benzyl-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

N-(Methoxymethyl)-N-(trimethylsilylmethyl) benzylamine (17.3 mL, 67.6 mmol) and TFA (3.4 mL) were added to a solution of 5-methoxy-inden-1-one (5.4 g, 33.8 mmol) in CH₂Cl₂ (165 mL) at 0° C. The reaction was stirred for 3 hours at room temperature and quenched with saturated aqueous NaHCO₃ (165 mL). The organic layer was separated, washed with brine (100 mL), dried over MgSO₄, and concentrated to afford the subtitle compound, which was used without further purification. MS calculated for C₁₉H₁₉NO₂+H: 294, observed: 294.

Step D. 2-Benzyl-5-methoxy-8-methylene-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Methyltriphenylphosphonium bromide (18.1 g, 50.7 mmol) and potassium tert-butoxide (5.7 g, 50.7) were added to a solution of 2-benzyl-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (9.9 g, 33.8 mmol) in anhydrous ether (68 mL). The reaction mixture was stirred for 1 hour at room temperature then filtered through celite. The celite was washed with ether (200 mL), and the filtrate was concentrated. The crude product was purified by column chromatography (SiO₂) using a 0-35% ethyl acetate-hexanes gradient to afford 8.1 g (82%—two steps) of the subtitle compound. MS calculated for C₂₀H₂₁NO+H: 292, observed: 292.

Step E. 5-Methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Ammonium formate (8.1 g) and palladium (10 wt. % on activated carbon, 4.0 g) were added to a solution of 2-benzyl-5-methoxy-8-methylene-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (8.1 g, 27.8 mmol) in MeOH (140 mL). The reaction mixture was stirred for 4 hours at 60° C. and then filtered through celite. The celite was washed with MeOH (200 mL) and the filtrate was concentrated to afford 5.6 g (quantitative yield) of the title compound. An aliquot of the crude product was purified by reverse-phase liquid chromatography to afford the title compound. MS calculated for C₁₃H₁₇NO+H: 204, observed: 204.

Example 2 5-Hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-Ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 1)

Hydrogen sodium carbonate (11.7 g, 139 mmol) and ethyl chloroformate (3.2 mL, 33.4 mmol) were added to a solution of 5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 1, Step E) (5.6 g, 27.8 mmol) in THF/H₂O (140 mL, 1/1, v/v), and stirred overnight at room temperature. The reaction mixture was quenched by addition of an aqueous HCl solution (200 mL, 1.0 M) and the product was extracted with EtOAc (3×100 mL). The combined organic extracts were dried over MgSO₄ and concentrated. The crude product was purified by column chromatography (SiO₂) using a 0-35% ethyl acetate-hexanes gradient to afford 2.7 g (35%) of the subtitle compound. ¹H NMR (CDCl₃ 300 MHz) * 7.07 (d, 1H), 6.78 (m, 2H), 4.09 (m, 2H), 3.79 (m, 5H), 3.63 (m, 1H), 3.52 (m, 1H), 3.32 (m, 1H), 3.07 (m, 1H), 2.95 (m, 1H), 1.26 (m, 6H) ppm. MS calculated for C₁₆H₂₁NO₃+H: 276, observed: 276.

Step B. 5-Hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

N-Ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (12 mg, 0.045 mmol) was dissolved in concentrated HCl (2 mL) and stirred for 20 hours at 120° C. The reaction solution was cooled to room temperature, diluted with H₂O (2 mL), and washed with EtOAc (5 mL). The aqueous solution was concentrated on a speed vac to afford the title compound as the hydrochloride salt. MS calculated for C₁₂H₁₅NO+H: 190, observed: 190.

Example 3 5-Methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-Ethylcarbamate-5-methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 1)

N-chlorosuccinimide (0.22 g, 1.6 mmol) and acetic acid (8 mL) were added to a solution of N-ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 2, Step A) (0.45 g, 1.6 mmol) in DCE (8 mL), and stirred for 3 hours at 60° C. The reaction mixture was cooled to room temperature, diluted with CH₂Cl₂ (50 mL), and washed with H₂O (50 mL). The organic extract was dried over MgSO₄ and concentrated. The crude product was purified by column chromatography (SiO₂) using a 0-35% ethyl acetate-hexanes gradient to afford 250 mg (51%) of the subtitle compound. MS calculated for C₁₆H₂₀ClNO₃+H: 310, observed: 310.

Step B. 5-Methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Barium hydroxide octahydrate (0.63 g, 2.0 mmol) was added to a solution of N-ethylcarbamate-5-methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (61 mg, 0.2 mmol) in MeOH (4 mL), and stirred for 24 hours at reflux. The reaction mixture was cooled to room temperature and neutralized to pH=7 with aqueous HCl (50 mL, 1 M). The product was extracted with CH₂Cl₂, dried over MgSO₄, and concentrated. The crude product was purified by reverse-phase liquid chromatography to afford the title compound. MS calculated for C₁₃H₁₆ClNO+H: 238, observed: 238.

Example 4 5-Hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

A solution of N-ethylcarbamate-5-methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 3, Step A) (61 mg, 0.2 mmol) in concentrated HCl was stirred overnight at 120° C. The reaction solution was cooled to room temperature and concentrated on a speed vac. The crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.04 (s, 1H), 6.73 (s, 1H), 3.52 (m, 1H), 3.22 (m, 2H), 2.83 (m, 3H), 2.41 (m, 1H), 1.18 (d, 3H) ppm. MS calculated for C₁₂H₁₄ClNO+H: 224, observed: 224.

Example 5 6-Chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-Ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 1)

BBr₃ (3.7 mL, 1.0 M in CH₂Cl₂) was added to a solution of N-ethylcarbamate-5-methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 3, Step A) (0.49 g, 1.6 mmol) in CH₂Cl₂ (32 mL), and stirred overnight at room temperature. The excess BBr₃ was quenched with the dropwise addition of H₂O (10 mL), and washed with saturated aqueous NaHCO₃ (50 mL) and brine (50 mL). The organic extract was dried over MgSO₄ and concentrated to afford the subtitle compound, which was used without further purification. MS calculated for C₁₅H₁₈ClNO₃+H: 296, observed: 296.

Step B. N-Ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole, O-trifluoromethanesulfonate

Pyridine (0.23 mL, 2.85 mmol) and trifluoromethanesulfonic anhydride (0.32 mL, 1.90 mmol) were added to a solution of N-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.28 g, 0.95 mmol) in CH₂Cl₂ (10 mL), and stirred for 1.5 hours at room temperature. The reaction was diluted with CH₂Cl₂ (10 mL), washed with H₂O (10 mL), aqueous HCl (1.0 M, 10 mL), saturated aqueous NaHCO₃(10 mL), and brine (10 mL). The organic extract was dried over MgSO₄ and concentrated to afford the subtitle compound, which was used without further purification. MS calculated for C₁₆H₁₇F₃ClNO₅S+H: 428, observed: 428.

Step C. N-Ethylcarbamate-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

To a mixture of N-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole, o-trifluoromethanesulfonate (60 mg, 0.14 mmol), palladium(II) acetate (6 mg, 0.028 mmol) and 1,3-bis(diphenylphosphino) propane (12 mg, 0.035 mmol) in MeOH (0.5 mL) and DMSO (0.5 mL) was added Et₃N (0.2 mL, 1.4 mmol). The resulting mixture was stirred for 2 hours at 80° C. then cooled to room temperature. The reaction mixture was diluted with EtOAc (5 mL) and then washed with H₂O (2 mL). The organic extract was dried over MgSO₄ and concentrated to afford 15 mg (35% yield) of the subtitle compound, which was used without further purification. MS calculated for C₁₅H₁₈ClNO₂+H: 280, observed: 280.

Step D. 6-Chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 4 using N-ethylcarbamate-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. The crude product was purified by reverse-phase liquid chromatography to afford the title compound. MS calculated for C₁₂H₁₄ClN+H: 208, observed: 208.

Example 6 5-(4-Fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-Ethylcarbamate-5-(4-fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 1)

4-Fluorobenzyl bromide (23 μL, 0.19 mmol) and potassium carbonate (100 mg, 0.78 mmol) were added to a solution of N-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 5, Step A) (46 mg, 0.16 mmol) in acetonitrile (3 mL), and stirred overnight at 80° C. The reaction was cooled to room temperature, concentrated by rotary evaporation and taken up in H₂O (5 mL). The product was extracted with EtOAc (3×10 mL). The combined organic extracts were dried over MgSO₄ and concentrated to afford the subtitle compound, which was used without further purification. MS calculated for C₂₂H₂₃ClFNO₃+H: 404, observed: 404.

Step B. 5-(4-Fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step B utilizing N-Ethylcarbamate-5-(4-fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. The crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.51 (m, 2H), 7.23 (m, 3H), 7.09 (s, 1H), 5.18 (m, 2H), 3.63 (m, 1H), 3.27 (m, 2H), 2.7-3.0 (m, 3H), 2.45 (m, 1H), 1.18 (d, 3H) ppm. MS calculated for C₁₉H₁₉ClFNO+H: 332, observed: 332.

Example 7 5-Benzyloxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-Ethylcarbamate-5-benzyloxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 1)

The subtitle compound was prepared by the method of Example 6, Step A utilizing N-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 5, Step A) and benzyl bromide. The crude product was obtained without further purification. MS calculated for C₂₂H₂₄ClNO₃+H: 386, observed: 386.

Step B. 5-Benzyloxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step B utilizing N-ethylcarbamate-5-benzyloxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydro-indeno[1,2-c]pyrrole. The crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.28-7.60 (m, 5H), 7.19 (s, 1H), 7.10 (s, 1H), 5.18 (m, 2H), 3.63 (m, 1H), 3.27 (m, 2H), 2.7-3.0 (m, 3H), 2.45 (m, 1H), 1.18 (d, 3H) ppm. MS calculated for C₁₉H₂₀ClNO+H: 314, observed: 314.

Example 8 5-(2-Fluorobenzyloxy)-6-chloro-8-methyl-1,2;3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-Ethylcarbamate-5-(2-fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 1)

The subtitle compound was prepared by the method of Example 6, Step A utilizing N-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 5, Step A) and 2-fluorobenzyl bromide. The crude product was obtained without further purification. MS calculated for C₂₂H₂₃ClFNO₃+H: 404, observed: 404.

Step B. 5-(2-Fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step B utilizing N-ethylcarbamate-5-(2-fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. The crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.58 (m, 1H), 7.44 (m, 1H), 7.25 (m, 2H), 7.19 (s, 1H), 7.09 (s, 1H), 5.20 (m, 2H), 3.63 (m, 1H), 3.27 (m, 2H), 2.7-3.0 (m, 3H), 2.45 (m, 1H), 1.22 (d, 3H) ppm. MS calculated for C₁₉H₁₉ClFNO+H: 332, observed: 332.

Example 9 5-(3-Fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-Ethylcarbamate-5-(3-Fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 1)

The subtitle compound was prepared by the method of Example 6, Step A utilizing N-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 5 Step A) and 3-fluorobenzyl bromide. The crude product was obtained without further purification. MS calculated for C₂₂H₂₃ClFNO₃+H: 404, observed: 404.

Step B. 5-(3-Fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step B utilizing N-ethylcarbamate-5-(3-fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. The crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.38 (m, 1H), 7.23 (m, 2H), 7.14 (m, 2H), 7.02 (s, 1H), 5.16 (m, 2H), 3.58 (m, 1H), 3.24 (m, 2H), 2.7-3.0 (m, 3H), 2.45 (m, 1H), 1.14 (d, 3H) ppm. MS calculated for C₁₉H₁₉ClFNO+H: 332, observed: 332.

Example 10 1,2,3,3a,8,8a-Hexahydroindeno[1,2-c]pyrrole

Step A. 2,2a,7,7a-Tetrahydro-cyclobuta[a]inden-1-one. (Scheme 2)

To a suspension of indene (1.2 mL, 10.0 mmol) and activated zinc (1.6 g, 25.0 mmol) in ether (100 mL) was added a solution of trichloroacetyl chloride (3.4 mL, 30.0 mmol) in ether (40 mL). The resulting mixture was stirred for 4 hours at reflux. The reaction was cooled to room temperature, filtered through celite, and the celite washed with ether (2×100 mL). The organic filtrate was washed with H₂O (100 mL), dried over MgSO₄, and concentrated.

The organic residue was dissolved in MeOH (100 mL). To this solution was added slowly zinc (5.0 g) and NH₄Cl (4.0 g). The reaction mixture was stirred overnight at reflux. The reaction mixture was cooled to room temperature, filtered through celite, the celite washed with MeOH (200 mL), and concentrated. The crude product was purified by column chromatography (SiO₂) using a 0-35% ethyl acetate-hexanes gradient to afford 1.4 g (89%—two steps) of the subtitle compound. ¹H NMR (CDCl₃ 300 MHz) * 7.24 (m, 4H), 4.06 (m, 2H), 3.63 (m, 1H), 3.29 (d, 1H), 3.10 (m, 1H), 2.88 (d, 1H) ppm.

Step B. 2,2a,7,7a-Tetrahydro-cyclobuta[a]inden-1-one oxime

Sodium acetate (1.45 g, 17.7 mmol) and hydroxyl amine hydrochloride (0.68 g, 9.75 mmol) were added to a solution of 2,2a,7,7a-tetrahydro-cyclobuta[a]inden-1-one (1.4 g, 8.86 mmol) in MeOH (18 mL), and stirred overnight at room temperature. The reaction solution was concentrated via rotary evaporation. The residue was dissolved in CH₂Cl₂ (100 mL), washed with H₂O (50 mL), dried over MgSO₄, and concentrated to give the subtitle compound, which was used without further purification. MS calculated for C₁₁H₁₁NO+H: 174, observed: 174.

Step C. 3,3a,8,8a-Tetrahydro-2H-2-aza-cyclopenta[a]inden-1-one

Thionyl chloride (1.9 mL, 26.4 mmol) was added to a solution of 2,2a,7,7a-tetrahydro-cyclobuta[a]inden-1-one oxime (1.5 g, 8.8 mmol) in 1,4-dioxane (44 mL), and stirred overnight at room temperature. The reaction was quenched with saturated aqueous NaHCO₃ (100 mL), and extracted with EtOAc (3×50 mL). The organic extracts were washed with brine, dried over MgSO₄, and concentrated to give the subtitle compound and its regioisomer, which were used without further purification. MS calculated for C₁₁H₁₁NO+H: 174, observed: 174.

Step D. 1,2,3,3a,8,8a-Hexahydroindeno[1,2-c]pyrrole

A solution of 3,3a,8,8a-tetrahydro-2H-2-aza-cyclopenta[a]inden-1-one (1.5 g, 8.8 mmol) in THF (44 mL) was cannulated to a solution of LAH in THF (26.4 mL, 1.0 M solution in THF). The resulting solution was stirred for 4 hours at 70° C., then overnight at room temperature. The reaction was quenched via the stepwise addition of H₂O (1 mL), aqueous NaOH (1 mL, 2.0 M solution), and H₂O (3 mL). The resulting mixture was filtered through celite, the celite washed with warm MeOH (200 mL), and the filtrate concentrated to give the subtitle compound and its regioisomer, which were used without further purification. MS calculated for C₁₁H₁₃N+H: 160, observed: 160.

Step E. N-tert-Butylcarbamate-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Di-tert-butyl dicarbonate (2.0 g, 9.4 mmol) and sodium hydrogen carbonate (4.0 g, 47 mmol) were added to a solution of 1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (1.5 g, 9.4 mmol) in H₂O/THF (46 mL, 1/1, v/v), and stirred overnight at room temperature. The reaction mixture was diluted with H₂O (50 mL), and extracted with EtOAc (3×100 mL). The combined organic extracts were dried over MgSO₄ and concentrated. The crude products (mixture of regioisomers) were purified and separated by column chromatography (SiO₂) using a 0-35% ethyl acetate-hexanes gradient to afford 110 mg (5% yield—5 steps) of the subtitle compound. MS calculated for C₁₆H₂₁NO₂+H: 260, observed: 260.

Step F. 1,2,3,3a,8,8a-Hexahydroindeno[1,2-c]pyrrole

N-tert-Butylcarbamate-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (110 mg, 0.42 mmol) was dissolved in a HCl solution (5 mL, 4.0 M solution in 1,4-dioxane) and stirred for 2 hours at room temperature. The reaction was concentrated by rotary evaporation. The crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.16 (m, 4H), 3.71 (m, 1H), 3.25 (m, 1H), 3.0-3.18 (m, 2H), 2.79-3.00 (m, 2H), 2.72 (m, 1H), 2.45 (m, 1H) ppm. MS calculated for C₁₁H₁₃N+H: 160, observed: 160.

Example 11 6-Chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 6-Chloro-1H-indene. (Scheme 2)

Sodium borohydride (2.3 g, 60.2 mmol) was added to a solution of 5-chloro-1-indanone (10.0 g, 60.2 mmol) in MeOH (300 mL), and stirred for 3 hours at room temperature. The reaction was quenched with H₂O (100 mL), and extracted with CH₂Cl₂ (3×100 mL). The combined extracts were dried over MgSO₄ and concentrated.

The organic residue was dissolved in toluene (300 mL) and treated with p-toluenesulfonic acid monohydrate (1.2 g, 6.02 mmol), which was stirred for 1 hour at 90° C. The reaction was cooled to room temperature, washed with brine (150 mL), dried over MgSO4, and concentrated to give 6.9 g (76%—two steps) of the subtitle compound, which was used without further purification.

Step B. 5-Chloro-2,2a,7,7a-tetrahydro-cyclobuta[a]inden-1-one

The subtitle compound was prepared by the method of Example 10, Step A utilizing 6-chloro-1H-indene (3.4 g, 22.6 mmol). The crude product was obtained without further purification.

Step C. 5-Chloro-2,2a,7,7a-tetrahydro-cyclobuta[a]inden-1-one oxime

The subtitle compound was prepared by the method of Example 10, Step B utilizing 5-chloro-2,2a,7,7a-tetrahydro-cyclobuta[a]inden-1-one (2.0 g, 10.4 mmol). The crude product was obtained without further purification. MS calculated for C₁₁H₁₀ClNO+H: 208, observed: 208.

Step D. 6-Chloro-3,3a,8,8a-tetrahydro-2H-2-aza-cyclopenta[a]inden-1-one

The subtitle compound was prepared by the method of Example 10, Step C utilizing 5-chloro-2,2a,7,7a-tetrahydro-cyclobuta[a]inden-1-one (2.0 g, 10.4 mmol) The crude product was obtained without further purification. MS calculated for C₁₁H₁₀ClNO+H: 208, observed: 208.

Step E. 6-Chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The subtitle compound was prepared by the method of Example 10, Step D utilizing 6-chloro-3,3a,8,8a-tetrahydro-2H-2-aza-cyclopenta[a]inden-1-one (2.0 g, 10.4 mmol). The crude product was obtained without further purification. MS calculated for C₁₁H₁₂ClN+H: 194, observed: 194.

Step F. N-tert-Butylcarbamate-6-chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The subtitle compound was prepared by the method of Example 10, Step E utilizing 6-chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (2.0 g, 10.4 mmol). The crude product was obtained without further purification. MS calculated for C₁₆H₂₀ClNO₂+H: 294, observed: 294.

Step G. 6-Chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-]pyrrole

The title compound was prepared by the method of Example 10, Step F utilizing N-tert-butylcarbamate-6-chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. The crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) δ 7.25 (m, 3H), 3.71 (m, 1H), 3.19 (m, 2H), 3.05 (m, 2H), 2.88 (m, 1H), 2.77 (m, 1H), 2.45 (m, 1H) ppm. MS calculated for C₁₁H₁₃ClN+H: 194, observed: 194.

Example 12 6-(2,6-Difluorophenyl)-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-tert-Butylcarbamate-6-(2,6-difluorophenyl)-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 2)

Triphenylphosphine (2 mg), palladium(II) acetate (1 mg), 2,6-difluorophenyl boronic acid (20 mg, 0.12 mmol), and aqueous sodium carbonate (0.15 mL, 0.3 mmol) were added to a solution of (N-tert-butylcarbamate-6-chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 11, Step F) (30 mg, 0.1 mmol) in acetonitrile (1 mL), and stirred for 24 h at 80° C. The reaction mixture was concentrated, diluted with EtOAc (5 mL) and washed with H₂O (5 mL). The organic extract was dried over MgSO₄ and concentrated to give the subtitle compound, which was used without further purification. MS calculated for C₂₂H₂₃F₂NO₂+H: 372, observed: 372.

Step B. 6-(2,6-Difluorophenyl)-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 10, Step F. The crude product was purified by reverse-phase liquid chromatography to afford the title compound. MS calculated for C₁₇H₁₅F₂N+H: 272, observed: 272.

Example 13 5-Methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-m-Tolyl-acrylic acid ethyl ester. (Scheme 3)

KHMDS (4.0 g, 20.0 mmol) was added to a solution of ethyl[bis(2,2,2-trifluoro-ethoxy)phosphinyl]acetate (4.7 mL, 20.0 mmol) and 18-crown-6 (10.6 g, 40.0 mmol) in THF (200 mL) at −78° C., and stirred for 30 minutes. m-Tolualdehyde (2.1 mL, 18 mmol) was added and the reaction mixture was stirred for 3 hours from −78° C. to room temperature. The reaction was quenched with aqueous hydrochloric acid (1 M solution, 100 mL), and the product was extracted with EtOAc (3×100 mL). The organic extracts were washed with brine (100 mL), dried over MgSO4, and concentrated to afford the subtitle compound, which was used without further purification. MS calculated for C₁₂H₁₄O₂+H: 191, observed: 191.

Step B. 1-Benzyl-4-m-tolyl-pyrrolidine-3-carboxylic acid ethyl ester

The subtitle compound was prepared by the method of Example 1, Step C utilizing 3-m-tolyl-acrylic acid ethyl ester (18.0 mmol). The crude product was purified by column chromatography (SiO₂) using a 10-50% ethyl acetate-hexanes gradient to afford 4.7 g (81%—two steps) of the subtitle compound. MS calculated for C₂₁H₂₅NO₂+H: 324, observed: 324.

Step C. 1-Benzyl-4-m-tolyl-pyrrolidine-3-carboxylic acid

1-Benzyl-4-m-tolyl-pyrrolidine-3-carboxylic acid ethyl ester (4.6 g, 14.5 mmol) was suspended in aqueous HCl (73 mL, 18.0 M), and stirred overnight at 80° C. The reaction mixture was concentrated via rotary evaporation and placed on the vacuum line. MS calculated for C₁₉H₂₁NO₂+H: 296, observed: 296.

Step D. 2-Benzyl-5-methyl-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

DMF (16 drops) and oxalyl chloride (4.1 mL, 43.5 mmol) were added to a solution of 1-benzyl-4-m-tolyl-pyrrolidine-3-carboxylic acid (4.3 g, 14.5 mmol) in CH₂Cl₂ (29 mL) at 0° C. The reaction mixture was stirred overnight at room temperature, then concentrated via rotary evaporation, and placed on the vacuum line without any purification.

A solution of the acid chloride intermediate in CH₂Cl₂ (29 mL) was added slowly to a solution of AlCl₃ (4.9 g, 43.5 mmol) in CH₂Cl₂ (29 mL) at 0° C. The reaction mixture was stirred for 3 hours from 0° C. to room temperature, then quenched via the slow addition of a saturated solution of sodium bicarbonate (290 mL). The product was extracted with CH₂Cl₂ (3×100 mL). The organic extracts were washed with brine, dried over MgSO₄, and concentrated. The crude product was purified by column chromatography (SiO₂) using a 10-50% ethyl acetate-hexanes gradient to afford 0.91 g (23%—two steps) of the subtitle compound and 0.12 g (3%—two steps) of the regioisomeric 2-benzyl-7-methyl-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one. MS calculated for C₁₉H₁₉NO+H: 278, observed: 278.

Step E. 2-Benzyl-5-methyl-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-5-methyl-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (3.2 mmol). The crude product was purified by silica plug eluting with ethyl acetate-hexanes (3/1, v/v) to afford 0.88 g (98%) of the subtitled compound. MS calculated for C₂₀H₂₁N+H: 276, observed: 276.

Step F. 5-Methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 1, Step E utilizing 2-benzyl-5-methyl-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (3.2 mmol). An aliquot of the crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 6.98 (m, 3H), 3.55 (m, 1H), 3.25 (m, 2H), 2.85 (m, 3H), 2.45 (m, 1H), 2.24 (s, 3H), 1.22 (d, 3H) ppm. MS calculated for C₁₃H₁₇N+H: 188, observed: 188.

Example 14 4-Methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-o-Tolyl-acrylic acid ethyl ester. (Scheme 3)

The subtitle compound was prepared by the method of Example 13, Step A utilizing o-tolualdehyde (9.0 mmol). The crude product was obtained without further purification. MS calculated for C₁₂H₁₄O₂+H: 191, observed: 191.

Step B. 1-Benzyl-4-o-tolyl-pyrrolidine-3-carboxylic acid ethyl ester

The subtitle compound was prepared by the method of Example 1, Step C utilizing 3-o-tolyl-acrylic acid ethyl ester (9.0 mmol). The crude product was purified by column chromatography (SiO₂) using a 10-50% ethyl acetate-hexanes gradient to afford 2.3 g (79%—two steps) of the subtitle compound. MS calculated for C₂₁H₂₅NO₂+H: 324, observed: 324.

Step C. 1-Benzyl-4-o-tolyl-pyrrolidine-3-carboxylic acid

The subtitle compound was prepared by the method of Example 13, Step C utilizing 1-benzyl-4-o-tolyl-pyrrolidine-3-carboxylic acid ethyl ester (7.1 mmol). The crude product was obtained without further purification. MS calculated for C₁₉H₂₁NO₂+H: 296, observed: 296.

Step D. 2-Benzyl-4-methyl-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 13, Step D utilizing 1-benzyl-4-o-tolyl-pyrrolidine-3-carboxylic acid (7.1 mmol). The crude product was purified by column chromatography (SiO₂) using a 15-60% EtOAc—hexanes gradient to afford 0.73 g (37%—two steps) of the subtitle compound. MS calculated for C₁₉H₁₉NO+H: 278, observed: 278.

Step E. 2-Benzyl-4-methyl-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-4-methyl-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (2.6 mmol). The crude product was purified by silica plug eluting with EtOAc -hexanes (3/1, v/v) to afford the subtitled compound. MS calculated for C₂₀H₂₁N+H: 276, observed: 276.

Step F. 4-Methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 1, Step E utilizing 2-benzyl-4-methyl-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (2.6 mmol). An aliquot of the crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.10 (m, 1H), 6.98 (m, 2H), 3.72 (m, 1H), 3.48 (m, 1H), 3.22 (m, 1H), 2.97 (m, 2H), 2.72 (m, 1H), 2.45 (m, 1H), 2.21 (s, 3H), 1.22 (d, 3H) ppm. MS calculated for C₁₃H₁₇N+H: 188, observed: 188.

Example 15 6-Methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-p-Tolyl-acrylic acid ethyl ester. (Scheme 3)

The subtitle compound was prepared by the method of Example 13, Step A utilizing p-tolualdehyde (4.5 mmol). The crude product was obtained without further purification. MS calculated for C₁₂H₁₄O₂+H: 191, observed: 191.

Step B. 1-Benzyl-4-p-tolyl-pyrrolidine-3-carboxylic acid ethyl ester

The subtitle compound was prepared by the method of Example 1, Step C utilizing 3-p-tolyl-acrylic acid ethyl ester (4.5 mmol). The crude product was purified by column chromatography (SiO₂) using a 10-60% EtOAc—hexanes gradient to afford 1.15 g (79%—two steps) of the subtitle compound. MS calculated for C₂₁H₂₅NO₂+H: 324, observed: 324.

Step C. 1-Benzyl-4-p-tolyl-pyrrolidine-3-carboxylic acid

The subtitle compound was prepared by the method of Example 13, Step C utilizing 1-benzyl-4-p-tolyl-pyrrolidine-3-carboxylic acid ethyl ester (3.6 mmol). The crude product was obtained without further purification. MS calculated for C₁₉H₂₁NO₂+H: 296, observed: 296.

Step D. 2-Benzyl-6-methyl-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 13, Step D utilizing 1-benzyl-4-p-tolyl-pyrrolidine-3-carboxylic acid (3.6 mmol). The crude product was purified by column chromatography (SiO₂) using a 15-60% EtOAc—hexanes gradient to afford 0.50 g (50%—two steps) of the subtitle compound. MS calculated for C₁₉H₁₉NO+H: 278, observed: 278.

Step E. 2-Benzyl-6-methyl-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-6-methyl-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (1.8 mmol). The crude product was purified by silica plug eluting with EtOAc—hexanes (3/1, v/v) to afford the subtitle compound. MS calculated for C₂₀H₂₁N+H: 276, observed: 276.

Step F. 6-Methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 1, Step E utilizing 2-benzyl-6-methyl-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (1.8 mmol). An aliquot of the crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.00 (m, 3H), 3.61 (m, 1H), 3.30 (m, 2H), 2.9 (m, 3H), 2.42 (m, 1H), 2.27 (s, 3H), 1.22 (d, 3H) ppm. MS calculated for C₁₃H₁₇N+H: 188, observed: 188.

Example 16 7-Methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 2-Benzyl-7-methyl-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene. (Scheme 3)

The subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-7-methyl-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (from Example 13, Step D, regioisomer) (0.43 mmol). The crude product was purified by silica plug eluting with EtOAc—hexanes (3/1, v/v) to afford the subtitle compound. MS calculated for C₂₀H₂₁N+H: 276, observed: 276.

Step B. 7-Methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 1, Step E utilizing 2-benzyl-7-methyl-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (0.43 mmol). An aliquot of the crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.05 (m, 3H), 3.62 (m, 1H), 3.39 (m, 2H), 2.99 (m, 3H), 2.77 (m, 1H), 2.28 (s, 3H), 1.27 (d, 3H) ppm. MS calculated for C₁₃H₁₇N+H: 188, observed: 188.

Example 17 4-Fluoro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-o-Fluoro-acrylic acid ethyl ester. (Scheme 3)

The subtitle compound was prepared by the method of Example 13, Step A utilizing 2-fluorobenzaldehyde (9.0 mmol). The crude product was obtained without further purification. MS calculated for C₁₁H₁₁FO₂+H: 195, observed: 195.

Step B. 1-Benzyl-4-o-fluoro-pyrrolidine-3-carboxylic acid ethyl ester

The subtitle compound was prepared by the method of Example 1, Step C utilizing 3-o-fluoro-acrylic acid ethyl ester (9.0 mmol). The crude product was purified by column chromatography (SiO₂) using a 10-50% EtOAc—hexanes gradient to afford the subtitle compound in quantitative yield. MS calculated for C₂₀H₂₂FNO₂+H: 328, observed: 328.

Step C. 1-Benzyl-4-o-fluoro-pyrrolidine-3-carboxylic acid

The subtitle compound was prepared by the method of Example 13, Step C utilizing 1-benzyl-4-o-fluoro-pyrrolidine-3-carboxylic acid ethyl ester (9.0 mmol). The crude product was obtained without further purification. MS calculated for C₁₈H₁₈FNO₂+H: 300, observed: 300.

Step D. 2-Benzyl-4-fluoro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 13, Step D utilizing 1-benzyl-4-o-fluoro-pyrrolidine-3-carboxylic acid (9.0 mmol). The crude product was purified by column chromatography (SiO₂) using a 0-50% EtOAc—hexanes gradient to afford 0.59 g (23%—four steps) of the subtitle compound. MS calculated for C₁₈H₁₆FNO+H: 282, observed: 282.

Step E. 2-Benzyl-4-fluoro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-4-fluoro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (2.1 mmol). The crude product was purified by silica plug eluting with EtOAc—hexanes (3/1, v/v) to afford the subtitle compound. MS calculated for C₂₉H₁₈FN+H: 280, observed: 280.

Step F. 4-Fluoro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 1, Step E utilizing 2-benzyl-4-fluoro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (2.1 mmol). An aliquot of the crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.26 (m, 1H), 6.99 (m, 2H), 3.83 (m, 1H), 3.39 (m, 2H), 2.99 (m, 3H), 2.51 (m, 1H), 1.26 (d, 3H) ppm. MS calculated for C₁₂H₁₄FN+H: 192, observed: 192.

Example 18 5-Fluoro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-m-Fluoro-acrylic acid ethyl ester. (Scheme 3)

The subtitle compound was prepared by the method of Example 13, Step A utilizing m-fluorobenzaldehyde (18.0 mmol). The crude product was obtained without further purification. MS calculated for C₁₁H₁₁FO₂+H: 195, observed: 195.

Step B. 1-Benzyl-4-m-fluoro-pyrrolidine-3-carboxylic acid ethyl ester

The subtitle compound was prepared by the method of Example 1, Step C utilizing 3-m-fluoro-acrylic acid ethyl ester (18.0 mmol). The crude product was purified by column chromatography (SiO₂) using a 10-50% EtOAc—hexanes gradient to afford the subtitle compound in quantitative yield. MS calculated for C₂₀H₂₂FNO₂+H: 328, observed: 328.

Step C. 1-Benzyl-4-m-fluoro-pyrrolidine-3-carboxylic acid

The subtitle compound was prepared by the method of Example 13, Step C utilizing 1-benzyl-4-m-fluoro-pyrrolidine-3-carboxylic acid ethyl ester (18.0 mmol). The crude product was obtained without further purification. MS calculated for C₁₈H₁₈FNO₂+H: 300, observed: 300.

Step D. 2-Benzyl-5-fluoro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 13, Step D utilizing 1-benzyl-4-m-fluoro-pyrrolidine-3-carboxylic acid (18.0 mmol). The crude product was purified by column chromatography (SiO₂) using a 0-50% EtOAc—hexanes gradient to afford 2.7 g (53%—four steps) of the subtitle compound. MS calculated for C₁₈H₁₆FNO+H: 282, observed: 282.

Step E. 2-Benzyl-5-fluoro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-5-fluoro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (9.6 mmol). The crude product was purified by silica plug eluting with EtOAc—hexanes (3/1, v/v) to afford the subtitle compound. MS calculated for C₂₉H₁₈FN+H: 280, observed: 280.

Step F. 5-Fluoro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 1, Step E utilizing 2-benzyl-5-fluoro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (9.6 mmol). An aliquot of the crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.18 (m, 1H), 7.02 (m, 2H), 3.68 (m, 1H), 3.33 (m, 2H), 2.98 (m, 3H), 2.45 (m, 1H), 1.21 (d, 3H) ppm. MS calculated for C₁₂H₁₄FN+H: 192, observed: 192.

Example 19 6-Fluoro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-p-Fluoro-acrylic acid ethyl ester. (Scheme 3)

The subtitle compound was prepared by the method of Example 13, Step A utilizing p-fluorobenzaldehyde (9.0 mmol). The crude product was obtained without further purification. MS calculated for C₁₁H₁₁FO₂+H: 195, observed: 195.

Step B. 1-Benzyl-4-p-fluoro-pyrrolidine-3-carboxylic acid ethyl ester

The subtitle compound was prepared by the method of Example 1, Step C utilizing 3-p-fluoro-acrylic acid ethyl ester (9.0 mmol). The crude product was purified by column chromatography (SiO₂) using a 10-50% EtOAc—hexanes gradient to afford the subtitle compound in quantitative yield. MS calculated for C₂₀H₂₂FNO₂+H: 328, observed: 328.

Step C. 1-Benzyl-4-p-fluoro-pyrrolidine-3-carboxylic acid

The subtitle compound was prepared by the method of Example 13, Step C utilizing 1-benzyl-4-p-fluoro-pyrrolidine-3-carboxylic acid ethyl ester (9.0 mmol). The crude product was obtained without further purification. MS calculated for C₁₈H₁₈FNO₂+H: 300, observed: 300.

Step D. 2-Benzyl-6-fluoro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 13, Step D utilizing 1-benzyl-4-p-fluoro-pyrrolidine-3-carboxylic acid (9.0 mmol). The crude product was purified by column chromatography (SiO₂) using a 0-50% EtOAc -hexanes gradient to afford 1.12 g (44%—four steps) of the subtitle compound. MS calculated for C₁₈H₁₆FNO+H: 282, observed: 282.

Step E. 2-Benzyl-6-fluoro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-6-fluoro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (4.0 mmol). The crude product was purified by silica plug eluting with EtOAc—hexanes (3/1, v/v) to afford the subtitle compound. MS calculated for C₂₉H₁₈FN+H: 280, observed: 280.

Step F. 6-Fluoro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 1, Step E utilizing 2-benzyl-5-fluoro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (4.0 mmol). An aliquot of the crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.18 (m, 1H), 6.99 (m, 2H), 3.62 (m, 1H), 3.29 (m, 2H), 2.87 (m, 3H), 2.45 (m, 1H), 1.22 (d, 3H) ppm. MS calculated for C₁₂H₁₄FN+H: 192, observed: 192.

Example 20 5-Chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-m-Chloro-acrylic acid ethyl ester. (Scheme 3)

The subtitle compound was prepared by the method of Example 13, Step A utilizing 3-chlorobenzaldehyde (9.0 mmol). The crude product was obtained without further purification. MS calculated for C₁₁H₁₁ClO₂+H: 211, observed: 211.

Step B. 1-Benzyl-4-m-chloro-pyrrolidine-3-carboxylic acid ethyl ester

The subtitle compound was prepared by the method of Example 1, Step C utilizing 3-m-chloro-acrylic acid ethyl ester (9.0 mmol). The crude product was purified by column chromatography (SiO₂) using a 10-50% EtOAc—hexanes gradient to afford the subtitle compound in quantitative yield. MS calculated for C₂₀H₂₂ClNO₂+H: 344, observed: 344.

Step C. 1-Benzyl-4-m-chloro-pyrrolidine-3-carboxylic acid

The subtitle compound was prepared by the method of Example 13, Step C utilizing 1-benzyl-4-m-chloro-pyrrolidine-3-carboxylic acid ethyl ester (9.0 mmol). The crude product was obtained without further purification. MS calculated for C₁₈H₁₈ClNO₂+H: 316, observed: 316.

Step D. 2-Benzyl-5-chloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 13, Step D utilizing 1-benzyl-4-m-chloro-pyrrolidine-3-carboxylic acid (9.0 mmol). The crude product was purified by column chromatography (SiO₂) using a 0-50% EtOAc—hexanes gradient to afford 0.59 g (22%—four steps) of the subtitle compound and 0.20 g (8%—four steps) of the regioisomeric 2-benzyl-7-chloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one. MS calculated for C₁₈H₁₆ClNO+H: 298, observed: 298.

Step E. 2-Benzyl-5-chloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-5-chloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (2.0 mmol). The crude product was purified by silica plug eluting with EtOAc—hexanes (3/1, v/v) to afford the subtitle compound. MS calculated for C₁₉H₁₈ClN+H: 296, observed: 296.

Step F. 5-Chloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

ACE-Cl (1.08 mL, 9.9 mmol) and K₂CO₃ (1.4 g, 9.9 mmol) were added to a solution of 2-benzyl-5-chloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (2.0 mmol) in DCE (10 mL) at 0° C. The reaction mixture was stirred for 30 minutes at 0° C., then overnight at 60° C. The reaction mixture was filtered through celite, the celite was washed with CH₂Cl₂, and the filtrate was concentrated.

The carbamate intermediate was dissolved in MeOH (10 mL) and stirred for 1 hour at 40° C. The solution was cooled to room temperature and concentrated via rotary evaporation. MS calculated for C₁₂H₁₂ClN+H: 206, observed: 206.

Step G. N-tert-Butyl carbamate-5-chloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

Di-tert-butyl dicarbonate (0.43 g, 2.00 mmol) and DIEA (1.0 mL, 6.0 mmol) were added to a solution of 5-chloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (2.0 mmol) in CH₂Cl₂ (10 mL) at 0° C. The reaction mixture was stirred for 2 hours at from 0° C. to room temperature, then quenched with aqueous HCl (10 mL, 0.1 M). The organic extracts were washed with brine, dried over MgSO₄, and concentrated to afford the subtitle compound in quantitative yield. MS calculated for C₁₇H₂₀ClNO₂+H: 306, observed: 306.

Step H. N-tert-Butyl carbamate-5-chloro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

N-tert-Butyl carbamate-5-chloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (0.6 g, 2.0 mmol) was dissolved in EtOAc (10 mL) and purged with N₂. Palladium on carbon (0.2 g, 10 wt. %) was added and the flask was purged with N₂, and then charged with a balloon of H₂. The reaction mixture was stirred for 2 hours at room temperature then filtered through celite. The celite was washed with EtOAc, and the filtrate was concentrated to afford the subtitle compound in quantitative yield. MS calculated for C₁₇H₂₂ClNO₂+H: 308, observed: 308.

Step I. 5-Chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

N-tert-Butyl carbamate-5-chloro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (10 mg, 0.03 mmol) was dissolved in an HCl solution (3 mL, 4 M in dioxane). The reaction was stirred for 2 hours at room temperature, and then concentrated to afford the title compound. An aliquot of the crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.21 (m, 3H), 3.68 (m, 1H), 3.31 (m, 2H), 2.92 (m, 3H), 2.45 (m, 1H), 1.22 (d, 3H) ppm. MS calculated for C₁₂H₁₄ClN+H: 208, observed: 208.

Example 21 5-Methyl-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-Ethylcarbamate-5-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 3)

Ethyl chloroformate (0.29 mL, 3.0 mmol) and DIEA (1.6 mL, 9.0 mmol) were added to a solution of 5-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 13, Step F) (0.56 g, 3.0 mmol) in CH₂Cl₂ (15 mL) at 0° C. The reaction was stirred for 2 hours from 0° C. to room temperature. The reaction was quenched with aqueous HCl (15 mL, 1M). The desired product was extracted with CH₂Cl₂ (3×15 mL). The organic extracts were washed with brine, dried over MgSO₄, and concentrated. The crude product was purified by column chromatography (SiO₂) using a 10-60% EtOAc—hexanes gradient to afford 0.36 g (46%) of the subtitle compound. MS calculated for C₁₆H₂₁NO₂+H: 260, observed: 260.

Step B. N-Ethylcarbamate-5-methyl-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

NCS (27 mg, 0.2 mmol) and acetic acid (1 mL) were added to a solution of N-Ethylcarbamate-5-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (50 mg, 0.2 mmol) in DCE (1 mL). The reaction solution was stirred for 3 hours at 60° C. The reaction was diluted with CH₂Cl₂ (3 mL) and H₂O (3 mL) and filtered through an Extrelut column. The column was washed with CH₂Cl₂ and the filtrate was concentrated. The crude product was purified by column chromatography (SiO₂) using a 0-60% ethyl acetate-hexanes gradient to afford the subtitle compound. MS calculated for C₁₆H₂₀ClNO₂+H: 294, observed: 294.

Step C. 5-Methyl-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step B utilizing N-Ethylcarbamate-5-methyl-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. The crude product was purified by reverse-phase liquid chromatography to afford the title compound. MS calculated for C₁₃H₁₆ClN+H: 222, observed: 222.

Example 22 5-Methyl-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-Ethylcarbamate-5-methyl-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 3)

NBS (34 mg, 0.2 mmol) was added to a solution of N-Ethylcarbamate-5-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 21, Step A) (50 mg, 0.2 mmol) in acetonitrile (1 mL), and stirred overnight at room temperature. The reaction was diluted with CH₂Cl₂ (3 mL) and H₂O (3 mL) and filtered through an Extrelut column. The column was washed with CH₂Cl₂ and the filtrate was concentrated. The crude product was purified by column chromatography (SiO₂) using a 0-50% EtOAc—hexanes gradient to afford the subtitle compound. MS calculated for C₁₆H₂₀BrNO₂+H: 338, observed: 338.

Step C. 5-Methyl-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step B utilizing N-Ethylcarbamate-5-methyl-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. The crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.29 (s, 1H), 7.12 (s, 1H), 3.70 (m, 3H), 2.92 (m, 3H), 2.45 (m, 1H), 2.29 (s, 3H), 1.22 (d, 3H) ppm. MS calculated for C₁₃H₁₆BrN+H: 266, observed: 266.

Example 23 5-Chloro-6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-Ethylcarbamate-6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 3)

The subtitle compound was prepared by the method of Example 21, Step A utilizing 6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 15, Step F) (1.8 mmol). The crude product was purified by column chromatography (SiO₂) using a 10-60% EtOAc—hexanes gradient to afford 0.25 g (54%) of the subtitle compound. MS calculated for C₁₆H₂₁NO₂+H: 260, observed: 260.

Step B. N-Ethylcarbamate-5-chloro-6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The subtitle compound was prepared by the method of Example 21, Step B utilizing N-Ethylcarbamate-6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.2 mmol). The crude product was purified by column chromatography (SiO₂) using a 0-60 EtOAc—hexanes gradient to afford the subtitle compound. MS calculated for C₁₆H₂₀ClNO₂+H: 294, observed: 294.

Step C. 5-Chloro-6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step B utilizing N-Ethylcarbamate-5-chloro-6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. The crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.21 (s, 1H), 7.10 (s, 1H), 3.61 (m, 1H), 3.29 (m, 2H), 2.88 (m, 3H), 2.45 (m, 1H), 2.29 (s, 3H), 1.22 (d, 3H) ppm. MS calculated for C₁₃H₁₆ClN+H: 222, observed: 222.

Example 24 5-Bromo-6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-Ethylcarbamate-5-bromo-6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 3)

The subtitle compound was prepared by the method of Example 22, Step A utilizing N-Ethylcarbamate-6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 23, Step A) (0.2 mmol). The crude product was purified by column chromatography (SiO₂) using a 0-50% EtOAc—hexanes gradient to afford the subtitle compound. MS calculated for C₁₆H₂₀BrNO₂+H: 338, observed: 338.

Step B. 5-Bromo-6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step B utilizing N-Ethylcarbamate-5-bromo-6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. The crude product was purified by reverse-phase liquid chromatography to afford the title compound. MS calculated for C₁₃H₁₆BrN+H: 266, observed: 266.

Example 25 4-Chloro-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-Ethylcarbamate-4-chloro-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 1)

N-chlorosuccinimide (0.39 g, 2.9 mmol) and acetic acid (3 mL) were added to a solution of N-ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 2, Step A) (0.80 g, 2.9 mmol) in DCE (3 mL). The resulting solution was stirred for 3 hours at 60° C. The reaction mixture was cooled to room temperature, diluted with CH₂Cl₂ (50 mL), and washed with H₂O (50 mL). The organic extract was dried over MgSO₄ and concentrated. The crude product was purified by column chromatography (SiO₂) using a 0-35% EtOAc—hexanes gradient to afford 50 mg (6%) of the subtitle compound (The major product is N-ethylcarbamate-5-methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole, 78%). MS calculated for C₁₆H₂₀ClNO₃+H: 310, observed: 310.

Step B. 4-Chloro-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step B utilizing N-Ethylcarbamate-4-chloro-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.16 mmol). The crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.08 (d, 1H), 6.98 (d, 1H), 3.81 (s, 3H), 3.64 (m, 1H), 3.47 (m, 1H), 3.29 (m, 1H), 2.91 (m, 3H), 2.45 (m, 1H), 1.21 (d, 3H) ppm. MS calculated for C₁₃H₁₆ClNO+H: 238, observed: 238.

Example 26 5,6-Dichloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-(3,4-Dichloro-phenyl)-acrylic acid ethyl ester. (Scheme 3)

The subtitle compound was prepared by the method of Example 13, Step A utilizing 3,4-dichlorobenzaldehyde (9.0 mmol). The crude product was obtained without further purification. MS calculated for C₁₁H₁₀Cl₂O₂+H: 245, observed: 245.

Step B. 1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester

The subtitle compound was prepared by the method of Example 1, Step C utilizing 3-(3,4-dichloro-phenyl)-acrylic acid ethyl ester (9.0 mmol). The crude product was purified by column chromatography (SiO₂) using a 10-50% EtOAc-hexanes gradient to afford the subtitle compound in quantitative yield. MS calculated for C₂₀H₂₂Cl₂NO₂+H: 378, observed: 378.

Step C. 1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid

The subtitle compound was prepared by the method of Example 13, Step C utilizing 1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (9.0 mmol). The crude product was obtained without further purification. MS calculated for C₁₈H₁₈Cl₂NO₂+H: 350, observed: 350.

Step D. 2-Benzyl-5,6-dichloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 13, Step D utilizing 1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid (9.0 mmol). The crude product was purified by column chromatography (SiO₂) using a 0-50% EtOAC-hexanes gradient to afford 0.59 g (20%—four steps) of the subtitle compound and 0.30 g (10%—four steps) of the regioisomeric 2-benzyl-6,7-dichloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one. MS calculated for C₁₈H₁₆Cl₂NO+H: 332, observed: 332.

Step E. 2-Benzyl-5,6-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-5,6-dichloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (0.9 mmol). The crude product was purified by silica plug eluting with EtOAc-hexanes (3/1, v/v) to afford the subtitle compound. MS calculated for C₁₉H₁₈Cl₂N+H: 330, observed: 330.

Step F. 5,6-Dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 20, Step F utilizing 2-benzyl-5,6-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (0.9 mmol). The crude product was obtained without further purification. MS calculated for C₁₂H₁₂Cl₂N+H: 240, observed: 240.

Step G. N-tert-Butyl carbamate-5,6-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 20, Step G utilizing 5,6-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (0.9 mmol). The crude product was obtained without further purification. MS calculated for C₁₇H₂₀Cl₂NO₂+H: 340, observed: 340.

Step H. N-tert-Butyl carbamate-5,6-dichloro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 20, Step H utilizing N-tert-butyl carbamate-5,6-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (0.9 mmol). The crude product was obtained without further purification. MS calculated for C₁₇H₂₂Cl₂NO₂+H: 342, observed: 342.

Step I. 5,6-Dichloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The subtitle compound was prepared by the method of Example 20, Step I utilizing N-tert-butyl carbamate-5,6-dichloro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene. An aliquot of the crude product was purified by reverse-phase liquid chromatography to afford the title compound. MS calculated for C₁₂H₁₄Cl₂N+H: 242, observed: 242.

Example 27 6,7-Dichloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 2-Benzyl-6,7-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene. (Scheme 3)

The subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-6,7-dichloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (from Example 26, Step D, regioisomer) (1.8 mmol). The crude product was purified by silica plug eluting with EtOAc-hexanes (3/1, v/v) to afford the subtitle compound. MS calculated for C₁₉H₁₈Cl₂N+H: 330, observed: 330.

Step B. 6,7-Dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 20, Step F utilizing 2-benzyl-6,7-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (1.8 mmol). The crude product was obtained without further purification. MS calculated for C₁₂H₁₂Cl₂N+H: 240, observed: 240.

Step C. N-tert-Butyl carbamate-6,7-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 20, Step G utilizing 6,7-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (0.9 mmol). The crude product was obtained without further purification. MS calculated for C₁₇H₂₀Cl₂NO₂+H: 340, observed: 340.

Step D. N-tert-Butyl carbamate-6,7-dichloro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 20, Step H utilizing N-tert-butyl carbamate-6,7-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (1.8 mmol). The crude product was obtained without further purification. MS calculated for C₁₇H₂₂Cl₂NO₂+H: 342, observed: 342.

Step E. 6,7-Dichloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 20, Step I utilizing N-tert-butyl carbamate-6,7-dichloro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene. An aliquot of the crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.46 (d, 1H), 7.20 (d, 1H), 3.68 (m, 1H), 3.51 (m, 1H), 3.23 (m, 1H), 3.08 (m, 1H), 3.88 (m, 3H), 1.37 (d, 3H) ppm. MS calculated for C₁₂H₁₄Cl₂N+H: 242, observed: 242.

Example 28 4,6-Dichloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-(2,4-Dichloro-phenyl)-acrylic acid ethyl ester. (Scheme 3)

The subtitle compound was prepared by the method of Example 13, Step A utilizing 3,4-dichlorobenzaldehyde (18.0 mmol). The crude product was obtained without further purification. MS calculated for C₁₁H₁₀Cl₂O₂+H: 245, observed: 245.

Step B. 1-Benzyl-4-(2,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester

The subtitle compound was prepared by the method of Example 1, Step C utilizing 3-(2,4-dichloro-phenyl)-acrylic acid ethyl ester (18.0 mmol). The crude product was purified by column chromatography (SiO₂) using a 10-50% EtOAc-hexanes gradient to afford the subtitle compound in quantitative yield. MS calculated for C₂₀H₂₂Cl₂NO₂+H: 378, observed: 378.

Step C. 1-Benzyl-4-(2,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid

The subtitle compound was prepared by the method of Example 13, Step C utilizing 1-benzyl-4-(2,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (18.0 mmol). The crude product was obtained without further purification. MS calculated for C₁₈H₁₈Cl₂NO₂+H: 350, observed: 350.

Step D. 2-Benzyl-4,6-dichloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 13, Step D utilizing 1-benzyl-4-(2,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid (18.0 mmol). The crude product was purified by column chromatography (SiO₂) using a 0-50% EtOAc-hexanes gradient to afford 1.5 g (25%—four steps) of the subtitle compound. MS calculated for C₁₈H₁₆Cl₂NO+H: 332, observed: 332.

Step E. 2-Benzyl-4,6-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-4,6-dichloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (4.5 mmol). The crude product was purified by silica plug eluting with EtOAc-hexanes (3/1, v/v) to afford the subtitle compound. MS calculated for C₁₉H₁₈Cl₂N+H: 330, observed: 330.

Step F. 4,6-Dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 20, Step F utilizing 2-benzyl-4,6-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (4.5 mmol). The crude product was obtained without further purification. MS calculated for C₁₂H₁₂Cl₂N+H: 240, observed: 240.

Step G. N-tert-Butyl carbamate-4,6-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 20, Step G utilizing 4,6-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (4.5 mmol). The crude product was obtained without further purification. MS calculated for C₁₇H₂₀Cl₂NO₂+H: 340, observed: 340.

Step H. N-tert-Butyl carbamate-4,6-dichloro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 20, Step H utilizing N-tert-butyl carbamate-4,6-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (0.9 mmol) to afford 0.33 g (22%—4 steps) of the subtitle compound. MS calculated for C₁₇H₂₂Cl₂NO₂+H: 342, observed: 342.

Step I. 4,6-Dichloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 20, Step I utilizing N-tert-butyl carbamate-4,6-dichloro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene. An aliquot of the crude product was purified by reverse-phase liquid chromatography to afford the title compound. MS calculated for C₁₂H₁₄Cl₂N+H: 242, observed: 242.

Example 29 5-Ethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-Ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 1)

BBr₃ (0.3 mL, 0.30 mmol, 1 M in CH₂Cl₂) was added to a solution of N-Ethylcarbamate-5-methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 3, Step A) (46 mg, 0.15 mmol) at 0 ° C., and stirred overnight at room temperature. The reaction solution was quenched with H₂O and filtered through an Extrelut column. The column was washed with CH₂Cl₂, and the filtrate was concentrated. The crude product was obtained without further purification. MS calculated for C₁₅H₁₈ClNO₃+H: 296, observed: 296.

Step B. N-Ethylcarbamate-5-ethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Bromoethane (17 mL, 0.23 mmol) and K₂CO₃ (105 mg, 0.75 mmol) were added to a solution of N-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (44 mg, 0.15 mmol) in CH₃CN (1.5 mL). The reaction was stirred overnight at 70° C., diluted with H₂O and CH₂Cl₂, and filtered through an Extrelut column. The column was washed with CH₂Cl₂ and the filtrate was concentrated. The crude product was obtained without further purification. MS calculated for C₁₇H₂₂ClNO₃+H: 324, observed: 324.

Step C. 5-Ethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step B utilizing N-ethylcarbamate-5-ethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.15 mmol). The crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.18 (s, 1H), 7.00 (s, 1H), 4.09 (m, 2H), 3.68 (m, 1H), 3.31 (m, 2H), 2.99 (m, 3H), 2.45 (m, 1H), 1.33 (t, 3H), 1.21 (d, 3H) ppm. MS calculated for C₁₄H₁₆ClNO+H: 252, observed: 252.

Example 30 5-Methoxy-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-Ethylcarbamate-5-methoxy-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 1)

NBS (70 mg, 0.4 mmol) was added to a solution of N-methylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 2, step A) (0.1 g, 0.36 mmol) in CH₃CN (3.6 mL), and stirred overnight at room temperature. The reaction was diluted with H₂O and EtOAc and filtered through an Extrelut column. The column was washed with EtOAc and the filtrate was concentrated to afford 120 mg (94%) of the subtitle compound. MS calculated for C₁₆H₂₀BrNO₃+H: 342, observed: 342.

Step B. 5-Methoxy-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step B utilizing N-ethylcarbamate-5-methoxy-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.17 mmol). The crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.29 (s, 1H), 6.93 (s, 1H), 3.81 (s, 3H), 3.61 (m, 1H), 3.28 (m, 2H), 2.98 (m, 1H), 2.83 (m, 2H), 2.45 (m, 1H), 1.33 (t, 3H), 1.21 (d, 3H) ppm. MS calculated for C₁₃H₁₆BrNO+H: 282, observed: 282.

Example 31 5-Hydroxy-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-Ethylcarbamate-5-hydroxy-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 1)

The subtitle compound was prepared by the method of Example 29, Step A utilizing N-ethylcarbamate-5-methoxy-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 30, Step A) (0.09 mmol). The crude product was obtained without further purification. MS calculated for C₁₅H₁₈BrNO₃+H: 340, observed: 340.

Step B. 5-Hydroxy-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step B utilizing N-ethylcarbamate-5-hydroxy-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.09 mmol). The crude product was purified by reverse-phase liquid chromatography to afford the title compound. MS calculated for C₁₂H₁₄BrNO+H: 268, observed: 268.

Example 32 5-Methoxy-6-(2-thienyl)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-Ethylcarbamate-5-methoxy-6-(2-thienyl)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 1)

Thiophene-2-boronic acid (44 mg, 0.34 mmol), Pd(PPh₃)₄ (19 mg, 0.02 mmol), K₂CO₃ (71 mg, 0.51 mmol), and H₂O (0.17 mL) were added to a solution of N-ethylcarbamate-5-methoxy-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 30, Step A) (60 mg, 0.17 mmol) in dioxane (3 mL) and stirred overnight at 100° C. The reaction mixture was diluted with EtOAC and H₂O, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via a silica plug eluting with Hexanes/EtOAc (2/1, v/v). MS calculated for C₂₀H₂₅NO₃S+H: 358, observed: 358.

Step B. 5-Methoxy-6-(2-thienyl)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step B utilizing N-ethylcarbamate-5-methoxy-6-(2-thienyl)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.17 mmol). The crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) *7.52 (d, 1H), 7.49 (d, 1H), 7.41 (s, 1H), 7.10 (t, 1H), 6.97 (s, 1H), 3.88 (s, 3H), 3.66 (m, 1H), 3.31 (m, 2H), 3.00 (m, 1H), 2.88 (m, 2H), 2.45 (m, 1H), 1.29 (d, 3H) ppm. MS calculated for C₁₇H₁₉NOS+H: 286, observed: 286.

Example 33 5-Methoxy-6-cyano-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-Ethylcarbamate-5-methoxy-6-cyano-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 1)

CuCN (68 mg, 0.85 mmol) was added to a solution of N-ethylcarbamate-5-methoxy-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 30, Step A) (60 mg, 0.17 mmol) in DMF (1.7 mL), and stirred overnight at 100° C. The reaction mixture was diluted with EtOAC and H₂O, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via a silica plug eluting with Hexanes/EtOAc (2/1, v/v). MS calculated for C₁₇H₂₀N₂O₃+H: 301, observed: 301.

Step B. 5-Methoxy-6-cyano-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step B utilizing N-ethylcarbamate-5-methoxy-6-cyano-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.17 mmol). The crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.44 (s, 1H), 7.04 (s, 1H), 3.88 (s, 3H), 3.65 (m, 1H), 3.23 (m, 2H), 2.88 (m, 1H), 2.78 (m, 2H), 2.40 (m, 1H), 1.21 (d, 3H) ppm. MS calculated for C₁₄H₁₆N₂O+H: 229, observed: 229.

Example 34 4,5-Dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-Bromo-4,5-dimethoxy-1-indanone. (Scheme 3)

The subtitle compound was prepared by the method of Example 1, Step A utilizing 4,5-dimethoxy-1-indanone (26.0 mmol). The crude product was obtained without further purification. MS calculated for C₁₁H₁₁BrO₃+H: 271, observed: 271.

Step B. 4,5-Dimethoxy-inden-1-one

The subtitle compound was prepared by the method of Example 1, Step B utilizing 3-bromo-4,5-dimethoxy-1-indanone (26.0 mmol). The crude product was obtained without further purification. MS calculated for C₁₁H₁₀O₃+H: 191, observed: 191.

Step C. 2-Benzyl-4,5-dimethoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 1, Step C utilizing 4,5-dimethoxy-inden-1-one (26.0 mmol). The crude product was purified by silica plug eluting with hexanes/EtOAc (3/1, v/v) to afford 4.2 g (50%—3 steps) of the subtitle compound. MS calculated for C₂₀H₂₁NO₃+H: 324, observed: 324.

Step D. 2-Benzyl-4,5-dimethoxy-8-methylene-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-4,5-dimethoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (13.0 mmol). The crude product was purified by silica plug eluting with hexanes/EtOAc (3/1, v/v) to afford the subtitle compound in quantitative yield. MS calculated for C₂₁H₂₃NO₂+H: 322, observed: 322.

Step E. 4,5-Dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The subtitle compound was prepared by the method of Example 1, Step E utilizing 2-benzyl-4,5-dimethoxy-8-methylene-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (13.0 mmol). The crude product was obtained without further purification. MS calculated for C₁₄H₁₉NO₂+H: 234, observed: 234.

Step F. N-Ethylcarbamate-4,5-dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The subtitle compound was prepared by the method of Example 2, Step A utilizing 4,5-dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (13.0 mmol). The crude product was purified by column chromatography (SiO₂) using a 0-50% EtOAc-hexanes gradient to afford the subtitle compound. MS calculated for C₁₇H₂₃NO₄+H: 306, observed: 306.

Step G. 4,5-Dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step B utilizing N-ethylcarbamate-4,5-dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.03 mmol). The crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 6.88 (d, 1H), 6.79 (d, 1H), 3.72 (m, 7H), 3.32 (m, 1H), 3.21 (m, 1H), 2.84 (m, 3H), 2.40 (m, 1H), 1.19 (d, 3H) ppm. MS calculated for C₁₄H₁₉NO₂+H: 234, observed: 234.

Example 35 4,5-Dimethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-Ethylcarbamate-4,5-dimethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 3)

The subtitle compound was prepared by the method of Example 3, Step A utilizing N-ethylcarbamate-4,5-dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 34, Step F) (0.58 mmol). The crude product was obtained without further purification. MS calculated for C₁₇H₂₂ClNO₄+H: 340, observed: 340.

Step B. 5-Methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step B utilizing N-ethylcarbamate-4,5-dimethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.12 mmol). The crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 6.88 (d, 1H), 6.79 (d, 1H), 3.72 (m, 7H), 3.32 (m, 1H), 3.21 (m, 1H), 2.84 (m, 3H), 2.40 (m, 1H), 1.19 (d, 3H) ppm. MS calculated for C₁₄H₁₈ClNO₂+H: 268, observed: 268.

Example 36 4,5-Dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-Bromo-5,6-dimethoxy-1-indanone. (Scheme 3)

The subtitle compound was prepared by the method of Example 1, Step A utilizing 5,6-dimethoxy-1-indanone (52.0 mmol). The crude product was obtained without further purification. MS calculated for C₁₁H₁₁BrO₃+H: 271, observed: 271.

Step B. 5,6-Dimethoxy-inden-1-one

The subtitle compound was prepared by the method of Example 1, Step B utilizing 3-bromo-5,6-dimethoxy-1-indanone (52.0 mmol). The crude product was obtained without further purification. MS calculated for C₁₁H₁₀O₃+H: 191, observed: 191.

Step C. 2-Benzyl-5,6-dimethoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 1, Step C utilizing 5,6-dimethoxy-inden-1-one (52.0 mmol). The crude product was purified by silica plug eluting with hexanes/EtOAc (3/1, v/v) to afford the subtitle compound. MS calculated for C₂₀H₂₁NO₃+H: 324, observed: 324.

Step D. 2-Benzyl-5,6-dimethoxy-8-methylene-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-5,6-dimethoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (3.1 mmol). The crude product was purified by silica plug eluting with hexanes/EtOAc (3/1, v/v) to afford the subtitle compound in quantitative yield. MS calculated for C₂₁H₂₃NO₂+H: 322, observed: 322.

Step E. 5,6-Dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The subtitle compound was prepared by the method of Example 1, Step E utilizing 2-benzyl-5,6-dimethoxy-8-methylene-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (3.1 mmol). The crude product was obtained without further purification. MS calculated for C₁₄H₁₉NO₂+H: 234, observed: 234.

Step F. N-tert-Butylcarbamate-4,5-dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The subtitle compound was prepared by the method of Example 20, Step G utilizing 5,6-dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (3.1 mmol). The crude product was purified by column chromatography (SiO₂) using a 0-50% EtOAc-hexanes gradient to afford the subtitle compound. MS calculated for C₁₉H₂₇NO₄+H: 334, observed: 334.

Step G. 4,5-Dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 20, Step H utilizing N-tert-butylcarbamate-5,6-dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno [1,2-c]pyrrole (0.15 mmol). The crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 6.92 (s, 1H), 6.80 (s, 1H), 3.72 (m, 7H), 3.55 (m, 1H), 3.21 (m, 4H), 2.65 (m, 1H), 1.26 (d, 3H) ppm. MS calculated for C₁₄H₁₉NO₂+H: 234, observed: 234.

Example 37 5-Methoxy-6-chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 2-Benzyl-5-methoxy-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]inden-8-ol. (Scheme 1)

NaBH₄ (0.27 g, 6.8 mmol) was added to a solution of 2-benzyl-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (from Example 1, Step C) (1.0 g, 3.4 mmol) in MeOH (17 mL), and stirred for 2 hours at room temperature. The reaction solution was concentrated via rotary evaporation and the residue dissolved in EtOAc. The organic solution was washed with a saturated aqueous NaHCO₃ solution and brine, dried over MgSO₄, and concentrated. The crude product was obtained without further purification. MS calculated for C₁₉H₂₁NO₂+H: 296, observed: 296.

Step B. 2-Benzyl-5-methoxy-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

InCl₃ (0.38 g, 1.7 mmol) and chlorodiphenylsilane (1.3 mL, 6.8 mmol) were added to a solution of 2-benzyl-5-methoxy-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]inden-8-ol (3.4 mmol) in DCE (17 mL), and stirred overnight at 60° C. The reaction mixture was washed with H₂O, a saturated aqueous NaHCO₃ solution and brine. The organic extracts were dried over MgSO₄ and concentrated. The crude product was obtained without further purification. MS calculated for C₁₃H₂₁NO+H: 280, observed: 280.

Step C. 5-Methoxy -1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The subtitle compound was prepared by the method of Example 1, Step E utilizing 2-benzyl-5-methoxy-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (3.4 mmol). The crude product was obtained without further purification. MS calculated for C₁₂H₁₅NO+H: 190, observed: 190.

Step D. N-Ethylcarbamate-5-methoxy-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The subtitle compound was prepared by the method of Example 2, Step A utilizing 5-methoxy-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (3.4 mmol). The crude product was purified by column chromatography (SiO₂) using a 0-50% EtOAc-hexanes gradient to afford the subtitle compound. MS calculated for C₁₆H₁₉NO₃+H: 262, observed: 262.

Step E. N-Ethylcarbamate-5-methoxy-6-chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The subtitle compound was prepared by the method of Example 3, Step A utilizing N-ethylcarbamate-5-methoxy-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.19 mmol). The crude product was obtained without further purification. MS calculated for C₁₆H₁₈ClNO₃+H: 296, observed: 296.

Step F. 5-Methoxy-6-chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step B utilizing N-ethylcarbamate-5-methoxy-6-chloro-8-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.19 mmol). The crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.17 (s, 1H), 6.97 (s, 1H), 3.81 (s, 3H), 3.62 (m, 1H), 3.00 (m, 5H), 2.60 (m, 2H) ppm. MS calculated for C₁₂H₁₄ClNO+H: 224, observed: 224.

Example 38 4,6-Dichloro-5-Methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-Ethylcarbamate-4,6-dichloro-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 1)

NCS (63 mg, 0.47 mmol) and acetic acid (1 mL) were added to a solution of N-ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 2, Step A) (43 mg, 0.16 mmol) in DCE (1 mL), and the reaction solution was stirred for 3 hours at 70° C. The reaction was quenched with H₂O and the solution filtered through an Extrelut column. The column was washed with CH₂Cl₂, and the filtrate was concentrated. The subtitle compound was obtained without further purification. MS calculated for C₁₆H₁₉Cl₂NO₃+H: 344, observed: 344.

Step B. 4,6-Dichloro-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step B utilizing N-Ethylcarbamate-4,6-dichloro-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.16 mmol). The crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.28 (s, 1H), 3.78 (s, 3H), 3.71 (m, 1H), 3.29 (m, 2H), 2.84 (m, 3H), 2.60 (m, 1H), 1.21 (d, 3H), ppm. MS calculated for C₁₃H₁₅Cl₂NO+H: 272, observed: 272.

Example 39 5-Cyclopropylmethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-Ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 1)

BBr₃ (1.1 mL, 1.0 M in dichloromethane) was added to a solution of N-ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 2, step A) (0.31 g, 1.1 mmol) in CH₂Cl₂ (10 mL) at 0° C., and stirred overnight. The excess BBr₃ was quenched with the dropwise addition of water (2 mL), and washed with saturated aqueous NaHCO₃ (10 mL) and brine (10 mL). The organic extract was dried over MgSO₄ and concentrated. The subtitle compound was obtained without further purification. MS calculated for C₁₅H₁₉NO₃+H: 262, observed: 262.

Step B. N-Ethylcarbamate-5-cyclopropylmethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

(Bromomethyl)cyclopropane (13 mg, 0.09 mmol) and K₂CO₃ (24 mg, 0.17 mmol) were added to a solution of N-ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (23 mg, 0.09 mmol) in CH₃CN, and stirred overnight at 80° C. The reaction mixture was diluted with H₂O and CH₂Cl₂, and filtered through an Extrelut column. The column was washed with CH₂Cl₂, and the filtrate was concentrated. The subtitle compound was obtained without further purification. MS calculated for C₁₉H₂₅NO₃+H: 316, observed: 316.

Step C. N-Ethylcarbamate-5-cyclopropylmethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

NCS (38 mg, 0.28 mmol) and acetic acid (1 mL) were added to a solution of N-ethylcarbamate-5-cyclopropylmethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (89 mg, 0.28 mmol) in DCE (2 mL), and the reaction solution was stirred for 3 hours at 70° C. The reaction was quenched with H₂O and the solution filtered through an Extrelut column. The column was washed with CH₂Cl₂, and the filtrate was concentrated. The subtitle compound was obtained without further purification. MS calculated for C₁₉H₂₄ClNO₃+H: 350, observed: 350.

Step D. 5-Cyclopropylmethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step B utilizing N-ethylcarbamate-5-cyclopropylmethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.32 mmol). The crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.14 (s, 1H), 6.9 (s, 1H), 3.88 (d, 2H), 3.24 (m, 3H), 2.84 (m, 3H), 2.45 (m, 1H), 1.21 (m, 4H), 0.58 (d, 2H), 0.32 (d, 2H) ppm. MS calculated for C₁₆H₂₀ClNO+H: 278, observed: 278.

Example 40 5-Trifluoromethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-(3-Trifluoromethoxy-phenyl)-acrylic acid ethyl ester. (Scheme 3)

The subtitle compound was prepared by the method of Example 13, Step A utilizing 3-(trifluoromethyl)benzaldehyde (12.5 mmol). The crude product was obtained without further purification. MS calculated for C₁₂H₁₁F₃O₃+H: 261, observed: 261.

Step B. 1-Benzyl-4-(3-trifluoromethoxy-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester

The subtitle compound was prepared by the method of Example 1, Step C utilizing 3-(3-trifluoromethoxy-phenyl)-acrylic acid ethyl ester (12.5.0 mmol). The crude product was purified by column chromatography (SiO₂) using a 10-50% EtOAc-hexanes gradient to afford 3.5 g (72%—two steps) of the subtitle compound. MS calculated for C₂₁H₂₂F₃NO₃+H: 394, observed: 394.

Step C. 1-Benzyl-4-(3-trifluoromethoxy-phenyl)-pyrrolidine-3-carboxylic acid

The subtitle compound was prepared by the method of Example 13, Step C utilizing 1-benzyl-4-(3-trifluoromethoxy-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (8.9 mmol). The crude product was obtained without further purification. MS calculated for C₁₉H₁₈F₃NO₃+H: 366, observed: 366.

Step D. 2-Benzyl-5-trifluoromethoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 13, Step D utilizing 1-benzyl-4-(3-trifluoromethoxy-phenyl)-pyrrolidine-3-carboxylic acid (8.9 mmol). The crude product was purified by column chromatography (SiO₂) using a 15-60% EtOAc-hexanes gradient to afford 0.50 g (16%—two steps) of the subtitle compound. MS calculated for C₁₉H₁₆F₃NO₂+H: 348, observed: 348.

Step E. 2-Benzyl-5-trifluoromethoxy-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-5-trifluoromethoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (0.5 mmol). The crude product was purified by silica plug eluting with EtOAc-hexanes (3/1, v/v) to afford the subtitled compound. MS calculated for C₂₀H₁₈F₃NO+H: 346, observed: 346.

Step F. 5-Trifluoromethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 1, Step E utilizing 2-benzyl-5-trifluoromethoxy-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (0.5 mmol). An aliquot of the crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.19 (m, 3H), 3.65 (m, 1H), 3.28 (m, 2H), 2.83 (m, 3H), 2.45 (m, 1H), 1.25 (d, 3H) ppm. MS calculated for C₁₃H₁₄F₃NO+H: 258, observed: 258.

Example 41 4,5-Dichloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-(2,3-Dichloro-phenyl)-acrylic acid ethyl ester

The subtitle compound was prepared by the method of Example 13, Step A utilizing 3,4-dichlorobenzaldehyde (29.0 mmol). The crude product was obtained without further purification. MS calculated for C₁₁H₁₀Cl₂O₂+H: 245, observed: 245.

Step B. 1-Benzyl-4-(2,3-dichloro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester

The subtitle compound was prepared by the method of Example 1, Step C utilizing 3-(2,3-dichloro-phenyl)-acrylic acid ethyl ester (29.0 mmol). The crude product was purified by column chromatography (SiO₂) using a 0-70% EtOAc-hexanes gradient to afford 5.3 g (49%—two steps) of the subtitle compound. MS calculated for C₂₀H₂₂Cl₂NO₂+H: 378, observed: 378.

Step C. 1-Benzyl-4-(2,3-dichloro-phenyl)-pyrrolidine-3-carboxylic acid

The subtitle compound was prepared by the method of Example 13, Step C utilizing 1-benzyl-4-(2,3-dichloro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (14.0 mmol). The crude product was obtained without further purification. MS calculated for C₁₈H₁₈Cl₂NO₂+H: 350, observed: 350.

Step D. 2-Benzyl-4,5-dichloro-2,3,3a,8a-tetrahydro-11-P2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 13, Step D utilizing 1-benzyl-4-(2,3-dichloro-phenyl)-pyrrolidine-3-carboxylic acid (14.0 mmol). The crude product was purified by column chromatography (SiO₂) using a 0-50% EtOAc-hexanes gradient to afford the subtitle compound. MS calculated for C₁₈H₁₆Cl₂NO+H: 332, observed: 332.

Step E. 2-Benzyl-4,5-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-4,5-dichloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (14.0 mmol). The crude product was purified by silica plug eluting with EtOAc-hexanes (3/1, v/v) to afford 1.7 g (35%—three steps) of the subtitle compound. MS calculated for C₁₉H₁₈Cl₂N+H: 330, observed: 330.

Step F. 4,5-Dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 20, Step F utilizing 2-benzyl-4,5-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (4.9 mmol). The crude product was obtained without further purification. MS calculated for C₁₂H₁₂Cl₂N+H: 240, observed: 240.

Step G. N-Ethyl carbamate-4,5-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 2, Step A utilizing 4,5-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (4.9 mmol). The crude product was purified by column chromatography (SiO₂) using a 0-60% EtOAc-hexanes gradient to afford 0.32 g (21%—two steps) of the subtitle compound. MS calculated for C₁₅H₁₅Cl₂NO₂+H: 312, observed: 312.

Step H. N-Ethyl carbamate-4,5-dichloro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 20, Step H utilizing N-ethyl carbamate-4,5-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (1.0 mmol). The crude product was purified by column chromatography (SiO₂) using a 0-60% EtOAc-hexanes gradient to afford 0.10 g (32%) of the subtitle compound. MS calculated for C₁₅H₁₇Cl₂NO₂+H: 314, observed: 314.

Step I. 4,5-Dichloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step B utilizing N-ethyl carbamate-4,5-dichloro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (0.06 mmol). An aliquot of the crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.46 (d, 1H), 7.16 (d, 1H), 3.76 (m, 1H), 3.36 (m, 2H), 2.85 (m, 3H), 2.45 (m, 1H), 1.23 (d, 3H) ppm. MS calculated for C₁₂H₁₃Cl₂N+H: 242, observed: 242.

Example 42 6-Chloro-7-fluoro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 3-(3-Fluoro-4-chloro-phenyl)-acrylic acid methyl ester. (Scheme 3)

The subtitle compound was prepared by the method of Example 13, Step A utilizing 3,4-dichlorobenzaldehyde (34.0 mmol). The crude product was obtained without further purification. MS calculated for C₁₀H₈ClFO₂+H: 215, observed: 215.

Step B. 1-Benzyl-4-(3-fluoro-4-chloro-phenyl)-pyrrolidine-3-carboxylic acid methyl ester

The subtitle compound was prepared by the method of Example 1, Step C utilizing 3-(3-fluoro-4-chloro-phenyl)-acrylic acid methyl ester (34.0 mmol). The crude product was purified by column chromatography (SiO₂) using a 0-45% EtOAc-hexanes gradient to afford 6.3 g (53%—two steps) of the subtitle compound. MS calculated for C₁₉H₁₉ClFNO₂+H: 348, observed: 348.

Step C. 1-Benzyl-4-(3-fluoro-4-chloro-phenyl)-pyrrolidine-3-carboxylic acid

The subtitle compound was prepared by the method of Example 13, Step C utilizing 1-benzyl-4-(2,3-dichloro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (18.1 mmol). The crude product was obtained without further purification. MS calculated for C₁₈H₁₇ClFNO₂+H: 334, observed: 334.

Step D. 2-Benzyl-6-chloro-7-fluoro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 13, Step D utilizing 1-benzyl-4-(3-fluoro-4-chloro-phenyl)-pyrrolidine-3-carboxylic acid (18.1 mmol). The crude product was purified by column chromatography (SiO₂) using a 0-50% EtOAc-hexanes gradient to afford the subtitle compound. MS calculated for C₁₈H₁₅ClFNO+H: 316, observed: 316.

Step E. 6-Chloro-7-fluoro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 20, Step F utilizing 2-benzyl-6-chloro-7-fluoro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (2.1 mmol). The crude product was obtained without further purification. MS calculated for C₁₁H₉ClFNO+H: 226, observed: 226.

Step F. N-Ethyl carbamate-6-chloro-7-fluoro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 2, Step A utilizing 6-chloro-7-fluoro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (2.2 mmol). The crude product was purified by column chromatography (SiO₂) using a 0-55% EtOAc-hexanes gradient to afford the subtitle compound in quantitative yield. MS calculated for C₁₄H₁₃ClFNO₃+H: 298, observed: 298.

Step G. N-Ethyl carbamate-6-chloro-7-fluoro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 2, Step A utilizing 4,5-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (1.5 mmol). The crude product was purified by column chromatography (SiO₂) using a 10-55% EtOAc-hexanes gradient to afford 0.43 g (66%—two steps) of the subtitle compound in quantitative yield. MS calculated for C₁₅H₁₅ClFNO₂+H: 296, observed: 296.

Step H. N-Ethyl carbamate-6-chloro-7-fluoro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene

The subtitle compound was prepared by the method of Example 20, Step H utilizing N-ethyl carbamate-6-chloro-7-fluoro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (0.2 mmol). The crude product was purified by column chromatography (SiO₂) using a 0-60% EtOAc-hexanes gradient to afford the subtitle compound in quantitative yield. MS calculated for C₁₅H₁₇ClFNO₂+H: 298, observed: 298.

Step I. 6-Chloro-7-fluoro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step B utilizing N-ethyl carbamate-6-chloro-7-fluoro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (0.06 mmol). An aliquot of the crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.30 (d, 1H), 7.19 (d, 1H), 3.92 (m, 1H), 3.65 (m, 1H), 3.44 (m, 2H), 3.30 (m, 2H), 2.88 (m, 1H), 1.33 (d, 3H) ppm. MS calculated for C₁₂H₁₃ClFN+H: 226, observed: 226.

Example 43 5-Benzyloxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-Ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 1)

BBr₃ in CH₂Cl₂ (1.1 mL, 1.1 mmol, 1 M) was added to a solution of N-Ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 2, Step A) (100 mg, 0.36 mmol) at 0° C. The reaction mixture was stirred overnight from 0° C. to room temperature and quenched with H₂O. The solution was filtered through an Extrelut column, the column was washed with CH₂Cl₂, and the filtrate was concentrated. The crude product was obtained without further purification. MS calculated for C₁₅H₁₉NO₃+H: 262, observed: 262.

Step B. N-Ethylcarbamate-5-benzyloxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Benzyl bromide (15 μL, 0.12 mmol) and K₂CO₃ (70 mg, 0.5 mmol) were added to a solution of N-ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (26 mg, 0.1 mmol) in CH₃CN (2 mL). The resulting mixture was stirred overnight at 80° C. The reaction was cooled to room temperature, concentrated by rotary evaporation and taken up in H₂O (2.5 mL). The product was extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over MgSO₄ and concentrated to afford the subtitle compound, which was used without further purification. MS calculated for C₂₂H₂₅NO₃+H: 352, observed: 352.

Step C. 5-Benzyloxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step B utilizing N-ethylcarbamate-5-benzyloxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.1 mmol). The crude product was purified by reverse-phase liquid chromatography to afford the title compound. MS calculated for C₁₉H₂₁NO+H: 280, observed: 280.

Example 44 5-(2-Fluorobenzyloxy)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-Ethylcarbamate-5-(2-fluorobenzyloxy)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 1)

The subtitle compound was prepared by the method of Example 43, Step B utilizing N-ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 43, Step A) (0.1 mmol) and 2-fluorobenzyl bromide. The crude product was obtained without further purification. MS calculated for C₂₂H₂₄FNO₃+H: 370, observed: 370.

Step B. 5-(2-Fluorobenzyloxy)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step B utilizing N-ethylcarbamate-5-(2-fluorobenzyloxy)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.1 mmol). The crude product was purified by reverse-phase liquid chromatography to afford the title compound. MS calculated for C₁₉H₂₀FNO+H: 298, observed: 298.

Example 45 5-(3-Fluorobenzyloxy)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-Ethylcarbamate-5-(3-fluorobenzyloxy)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 1)

The subtitle compound was prepared by the method of Example 43, Step B utilizing N-ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 43, Step A) (0.1 mmol) and 3-fluorobenzyl bromide. The crude product was obtained without further purification. MS calculated for C₂₂H₂₄FNO₃+H: 370, observed: 370.

Step B. 5-(3-Fluorobenzyloxy)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step B utilizing N-ethylcarbamate-5-(3-fluorobenzyloxy)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.1 mmol). The crude product was purified by reverse-phase liquid chromatography to afford the title compound. MS calculated for C₁₉H₂₀FNO+H: 298, observed: 298.

Example 46 5-(4-Fluorobenzyloxy)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-Ethylcarbamate-5-(4-fluorobenzyloxy)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 1)

The subtitle compound was prepared by the method of Example 43, Step B utilizing N-ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 43, Step A) (0.1 mmol) and 4-fluorobenzyl bromide. The crude product was obtained without further purification. MS calculated for C₂₂H₂₄FNO₃+H: 370, observed: 370.

Step B. 5-(4-Fluorobenzyloxy)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step B utilizing N-ethylcarbamate-5-(4-fluorobenzyloxy)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.1 mmol). The crude product was purified by reverse-phase liquid chromatography to afford the title compound. MS calculated for C₁₉H₂₀FNO+H: 298, observed: 298.

Example 47 5-(2,6-bifluorophenyl)-8-methyl-1,2,3,3a,8,6a-hexahydroindeno[1,2-c]pyrrole

Step A. N-Ethylcarbamate-5-triflate-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 1)

Pyridine (0.9 mL, 1.08 mmol) and trifluoromethanesulfonic anhydride (0.12 mL, 0.72 mmol) were added to a solution of N-ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 43, Step A) (94 mg, 0.36 mmol) in CH₂Cl₂ (4 mL) at 0° C. The reaction solution was stirred for 2 hours from 0° C. to room temperature, then diluted with CH₂Cl₂. The crude product was washed with aqueous HCl (1 M), saturated aqueous NaHCO₃, and brine. The organic extracts were dried over MgSO₄ and concentrated to afford 52 mg (58%) of the subtitle compound. MS calculated for C₁₆H₁₈F₃NO₅S+H: 394, observed: 394.

Step B. N-Ethylcarbamate-5-(2,6-difluorophenyl)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

2,6-Difluorophenylboronic acid (41 mg, 0.26 mmol), Pd(dppf) (5 mg), and Et₃N (0.2 mL) were added to a solution of N-ethylcarbamate-5-triflate-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (52 mg, 0.13 mmol) in DME (2.6 mL), and stirred overnight at 90° C. The solution was cooled to room temperature, partitioned between CH₂Cl₂ and H₂O, and filtered through an Extrelut column. The column was washed with CH₂Cl₂, and the filtrate was concentrated. The crude product was obtained without further purification. MS calculated for C₂₁H₂₁F₂NO₂+H: 358, observed: 358.

Step C. 5-(2,6-Difluorophenyl)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 2, Step B utilizing N-ethylcarbamate-5-(2,6-difluorophenyl)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.1 mmol). The crude product was purified by reverse-phase liquid chromatography to afford the title compound. MS calculated for C₁₈H₁₇F₂N+H: 286, observed: 286.

Example 48 5-Methoxy-8-ethyl-1,2,3,3e,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. 2-Benzyl-5-methoxy-8-ethylene-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 1)

Ethyltriphenylphosphonium bromide (0.6 g, 1.6 mmol) and potassium tert-butoxide (0.18 g, 1.6 mmol) were added to a solution of 2-benzyl-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (from Example 1, Step C) (0.32 g, 1.1 mmol) in anhydrous ether (2.2 mL). The reaction mixture was stirred for 1 hour at room temperature then filtered through celite. The celite was washed with ether (10 mL), and the filtrate was concentrated. The crude product was purified by column chromatography (SiO₂) using a 0-35% EtOAc-hexanes gradient to afford the subtitle compound in quantitative yield. MS calculated for C₂₁H₂₃NO+H: 306, observed: 306.

Step B. 5-Methoxy-8-ethyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Ammonium formate (0.3 g) and palladium (10 wt. % on activated carbon, 0.3 g) were added to a solution of 2-benzyl-5-methoxy-8-ethylene-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.34 g, 1.1 mmol) in MeOH (5 mL). The reaction mixture was stirred for 4 hours at 60° C. and then filtered through celite. The celite was washed with MeOH (20 mL) and the filtrate was concentrated. The crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.05 (d, 1H), 6.75 (m, 2H), 3.69 (s, 3H), 3.58 (m, 1H), 3.28 (m, 1H), 3.05 (m, 1H), 2.90 (m, 3H), 2.31 (m, 1H), 2.05 (m, 1H), 1.28 (m, 1H), 1.05 (t, 3H) ppm. MS calculated for C₁₄H₁₉NO+H: 218, observed: 218.

Example 49 5-Hydroxy-8-ethyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-Ethylcarbamate-5-methoxy-8-ethyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 1)

Ethyl chloroformate (0.16 mL, 1.65 mmol) was added to a solution of 5-methoxy-8-ethyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 48, Step B) (0.24 g, 1.1 mmol) in CH₂Cl₂ (6 mL) at 0° C. The resulting solution was stirred overnight at room temperature. The reaction mixture was quenched with aqueous HCl solution (20 mL, 1.0 M) and the product was extracted with EtOAc (3×10 mL). The combined organic extracts were dried over MgSO₄ and concentrated. The crude product was purified by column chromatography (SiO₂) using a 0-35% EtOAc-hexanes gradient to afford 40 mg (13%) of the subtitle compound. MS calculated for C₁₇H₂₃NO₃+H: 290, observed: 290.

Step B. 5-Hydroxy-8-ethyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 2, Step B utilizing N-ethylcarbamate-5-hydroxy-8-ethyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.07 mmol). The crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 6.98 (d, 1H), 6.59 (m, 2H), 3.68 (m, 1H), 3.44 (m, 1H), 3.05 (m, 4H), 2.45 (m, 1H), 1.98 (m, 1H), 1.25 (m, 1H), 1.05 (t, 3H) ppm. MS calculated for C₁₃H₁₇NO+H: 204, observed: 204.

Example 50 5,6(2-(3-methyl)furan)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-Ethylcarbamate-5-methoxy-6-iodo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 1)

Icl (0.12 g, 0.72 mmol) and CaCO₃ (72 mg, 0.72 mmol) were added to a solution of N-ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 2, Step A) (0.1 g, 0.36 mmol) in MeOH (3.6 mL), and stirred overnight at room temperature. The reaction mixture was filtered through celite, the celite was washed with MeOH, and the filtrate concentrated. The crude material was dissolved in EtOAc, and washed with aqueous sodium bisulfite (5% solution) and brine. The organic extracts were dried over MgSO4 and brine. The crude product was purified via silica plug eluting with Hexanes/EtOAc (3/1, v/v) to afford 0.14 g (97%) of the subtitle compound. MS calculated for C16H20INO₃+H: 402, observed: 402.

Step B. N-Ethylcarbamate-5-hydroxy-6-iodo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

BBr₃ (0.7 mL, 0.7 mmol, 1 M in CH₂Cl₂) was added to a solution of N-ethylcarbamate-5-methoxy-6-iodo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (120 mg, 0.3 mmol) at 0° C. The reaction mixture was stirred overnight from 0° C. to room temperature and quenched with H₂O. The solution was filtered through an Extrelut column, the column was washed with CH₂Cl₂, and the filtrate was concentrated. The crude product was obtained without further purification. MS calculated for C₁₅H₁₈INO₃+H: 388, observed: 388.

Step C. N-Ethylcarbamate-5-allyloxy-6-iodo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Allyl bromide (52 μL, 0.6 mmol) and DBU (65 μL, 0.6 mmol) were added to a solution of N-ethylcarbamate-5-hydroxy-6-iodo-8-ethyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (116 mg, 0.3 mmol) in CH₂Cl₂ (3 mL), and stirred 2 hours at room temperature. The reaction solution was diluted with H₂O and filtered through an Extrelut column. The column was washed with CH₂Cl₂ and the filtrate was concentrated. The crude product was purified via silica plug eluting with Hexanes/EtOAc (3/1, v/v) to afford 50 mg (39%—two steps) of the subtitle compound. MS calculated for C₁₈H₂₂INO₃+H: 428, observed: 428.

Step D. N-Ethylcarbamate-5,6(2-(3-methyl)furan)-8-Methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

KOAc (40 mg, 0.36 mmol), nBu₄NBr (50 mg, 0.12 mmol), PPh₃ (3 mg, 0.1 mmol), and Pd(OAc)₂ (2 mg, 6 μmol) were added to a solution of N-ethylcarbamate-5-allyloxy-6-iodo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (50 mg, 0.12 mmol) in DMF (1 mL), and stirred overnight at 100 EC. The reaction solution was diluted with H₂O and CH₂Cl₂, and filtered through an Extrelut column. The column was washed with CH₂Cl₂ and the filtrate was concentrated. The crude product was obtained without further purification. MS calculated for C₁₈H₂₁NO₃+H: 300, observed: 300.

Step E. 5,6(2-(3-Methyl)furan)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

The title compound was prepared by the method of Example 3, Step B utilizing N-ethylcarbamate-5,6(2-(3-methyl)furan)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.1 mmol). The crude product was purified by reverse-phase liquid chromatography to afford the title compound. MS calculated for C₁₅H₁₇₀NO+H: 228, observed: 228.

Example 51 5-Methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The title compound was prepared by the method of Example 1, Step E utilizing 2-benzyl-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (from Example 1, Step C) (2.1 mmol). The crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.48 (d, 1H), 7.12 (d, 1H), 6.95 (dd, 1H), 3.87 (s, 3H), 3.72 (m, 1H), 2.98 (m, 4H), 2.81 (m, 1H) ppm. MS calculated for C₁₂H₁₃NO₂+H: 204, observed: 204.

Example 52 4-Chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

Step A. N-Ethyl carbamate-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one. (Scheme 1)

Ethyl chloroformate (0.18 mL, 1.9 mmol) and DIEA (1.0 mL, 5.7 mmol) were added to a solution of 5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (from Example 51) (0.38 g, 1.9 mmol) in CH₂Cl₂ (10 mL) at 0° C., and stirred overnight at room temperature. The reaction was quenched with aqueous HCl (1 M) and washed with briny. The organic extracts were dried over MgSO₄, and concentrated. The crude product was obtained without further purification. MS calculated for C₁₅H₁₇NO₄+H: 276, observed: 276.

Step B. N-Ethyl carbamate-4-chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

NCS (0.25 g, 1.9 mmol) and acetic acid (10 mL) were added to a solution of ethyl carbamate-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (0.52 g, 1.9 mmol) in DCE (10 mL), and stirred overnight at 60° C. The reaction was quenched with aqueous HCl (1 M) and washed with brine. The organic extracts were dried over MgSO₄, and concentrated. The crude product was purified by column chromatography (SiO₂) using a 0-60% EtOAc-hexanes gradient to afford the subtitle compound as a mixture of regioisomers. MS calculated for C₁₅H₁₆ClNO₄+H: 310, observed: 310.

Step C. 4-Chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 2, Step B utilizing N-ethyl carbamate-4-chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (0.32 mmol). The crude product was obtained without further purification as a mixture of regioisomers. MS calculated for C₁₂H₁₂ClNO₂+H: 238, observed: 238.

Step D. N-tert-butyl carbamate-4-chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The subtitle compound was prepared by the method of Example 20, Step G utilizing 4-chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (1.02 mmol). The crude product was purified and separated by column chromatography (SiO₂) using a 0-60% EtOAc-hexanes gradient to afford the subtitle compound and its regioisomer, N-tert-butyl carbamate-5-methoxy-6-chloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one. MS calculated for C₁₇H₂₀ClNO₄+H: 338, observed: 338.

Step E. 4-Chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The title compound was prepared by the method of Example 20, Step I utilizing N-tert-butyl carbamate-4-chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (0.10 mmol). The crude product was purified by reverse-phase liquid chromatography to afford the title compound. ¹H NMR (d₆-DMSO 300 MHz) * 7.70 (d, 1H), 7.47 (d, 1H), 4.18 (m, 1H), 4.00 (s, 3H), 3.65 (m, 2H), 3.58 (m, 2H), 3.45 (m, 1H) ppm. MS calculated for C₁₂H₁₂ClNO₂+H: 238, observed: 238.

Example 53 5-Methoxy-6-chloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one

The title compound was prepared by the method of Example 20, Step I utilizing N-tert-butyl carbamate-5-methoxy-6-chloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (from Example 52, Step D) (0.10 mmol). The crude product was purified by reverse-phase liquid chromatography to afford the title compound. MS calculated for C₁₂H₁₂ClNO₂+H: 238, observed: 238.

Example 54 4-Chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-ol

Step A. N-tert-Butyl carbamate-4-chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-ol. (Scheme 1)

NaBH₄ (4 mg, 0.1 mmol) was added to a solution of N-tert-butyl carbamate-4-chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (from Example 52, Step D) (20 mg, 0.06 mmol) in MeOH (2 mL), and stirred for 1 hour at room temperature. The reaction was partitioned between H₂O and CH₂Cl₂, and filtered through an Extrelut column. The column was washed with CH₂Cl₂, and the filtrate was concentrated. The crude product was obtained without further purification as a mixture of diastereomers. MS calculated for C₁₇H₂₂ClNO₄+H: 340, observed: 340.

Step B. 4-Chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-ol

The title compound was prepared by the method of Example 20, Step I utilizing N-tert-butyl carbamate-4-chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-ol (0.10 mmol). The crude product was purified by reverse-phase liquid chromatography to afford the title compound. MS calculated for C₁₂H₁₂ClNO₂+H: 240, observed: 240.

Example 55 5-Methoxy-6-chloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-ol

Step A. N-tert-Butyl carbamate-5-methoxy-6-chloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-ol

NaBH₄ (4 mg, 0.1 mmol) was added to a solution of N-tert-butyl carbamate-5-methoxy-6-chloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (from Example 52, Step D, regioisomer) (20 mg, 0.06 mmol) in MeOH (2 mL), and stirred for 1 hour at room temperature. The reaction was partitioned between H₂O and CH₂Cl₂, and filtered through an Extrelut column. The column was washed with CH₂Cl₂, and the filtrate was concentrated. The crude product was obtained without further purification as a mixture of diastereomers. MS calculated for C₁₇H₂₂ClNO₄+H: 340, observed: 340.

Step B. 5-Methoxy-6-chloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-ol

The title compound was prepared by the method of Example 20, Step I utilizing N-tert-butyl carbamate-4-chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-ol (0.10 mmol). The crude product was purified by reverse-phase liquid chromatography to afford the title compound. MS calculated for C₁₂H₁₂ClNO₂+H: 240, observed: 240.

Example 56 Separation of Enantiomers for Selected Compounds of the Invention

The following compounds were separated into their respective enantiomers using a 10 mm×250 mm Chiral Pak AD-RH chiral column.

Retention Time Final Products Derived Compound Column Conditions Enantiomer (minutes) from Enantiomer Example 2, Step A H₂O:CH₃CN (55:45) 1 13.70 2, 5, 38 2.6 mL/min 2 19.24 1, 2, 3, 4, 5, 6, 25, 29, 30, 31, 32, 33, 38, 43, 44, 45, 46, 47, 50 Example 21, Step A H₂O:CH₃CN (50:50) 1 30.57 21 2.0 mL/min 2 32.70 21 Example 23, Step A H₂O:CH₃CN (40:60) 1 17.34 15, 23 2.0 mL/min 2 21.49 15, 23 Example 26, Step H H₂O:CH₃CN (40:60) 1 28.47 26 2.0 mL/min 2 31.17 26 Example 27, Step D MeOH 1 10.30 27 10.0 mL/min 2 12.13 27 Example 34, Step F H₂O:CH₃CN (50:50) 1 23.02 34, 35 1.8 mL/min 2 26.44 34, 35 Example 36, Step F H₂O:CH₃CN (45:55) 1 16.00 36 1.8 mL/min 2 23.25 36 Example 37, Step D H₂O:CH₃CN (45:55) 1 20.42 37 1.8 mL/min 2 28.95 37 Example 41, Step H MeOH 1 9.92 41 10.0 mL/min 2 10.75 41 Example 42, Step H MeOH 1 8.05 42 10.0 mL/min 2 11.72 42

The following procedure was utilized to evaluate representative compounds of the present invention as 5HT_(2c) receptor agonists. The results of this assay are set forth in Table 1.

Cell Culture

HEK 293 EBNA expressing the human 5HT2c receptor (VSV Isoform; Burns et al., NATURE 387:30308, 1997) were grown in DMEM containing 10% dialysed FBS, 9 μg/ml blasticidin at 37° C. in 5% CO₂ atmosphere.

Calcium Mobilization

HEK 293 EBNA cells expressing human 5HT2_(c) receptor (2×10⁴/well) were seeded in black 384-well collagen coated plates and incubated overnight at 37° C. in a 5% CO2/95% atmosphere. After removing medium, cells were treated with HBSS buffer (137 mM NaCl, 5.4 mM KCl, 5.5 mM Glucose, 20 mM Hepes, pH 7.5, 2.1 mM MgCl₂, 0.3 mM CaCl₂, 0.02 mM MgSO₄, 3.0 mM NaHCO₃, and 0.64 mM KH₂PO₄) containing the Calcium3 dye (Molecular Device, CA), 2.5 mM probenecid and 0.08% pluronic acid for 60 minutes according to manufacture's instruction. Compounds that were solubilized in 100% DMSO were diluted in CsCl Ringers buffer (58.3 mM CsCl, 5.4 mM KCl, 5.5 mM Glucose, 20 mM Hepes, pH 7.5, 2.1 mM MgCl₂, 1.2 mM CaCl₂) such that the final DMSO concentration did not exceed 5%. 5HT was utilized as a positive control. Ligand induced calcium release and consequent fluorescence was measured on a Fluorometric Imaging Plate Reader (FLIPR, Molecular Device, CA).

Data Analysis

All data were analyzed by nonlinear least square curve fitting using Prism 4.0 software. Agonist stimulation of calcium-induced fluorescence in FLIPR was fitted to sigmoidal dose response using equation Y=Bottom+(Top−Bottom)/(1+10̂((Log EC50−X))), where X is the logarithm of concentration of compounds and Y is the fluorescent response.

5-HT2c Example EC50 Number Molecule (hVSV, μM) 1 1, Enantiomer 2

 >10  <1 2 2, Enantiomer 1 2, Enantiomer 2

<0.1   <1 <0.1 3 3, Enantiomer 2

<0.1 <0.1 4 4, Enantiomer 2

  <1 <0.1 5 5, Enantiomer 1 5, Enantiomer 2

<0.1   <1   <1 6 6, Enantiomer 2

  <1   <1 7

 <10 8

 <10 9

 <10 10

 <10 11

<0.1 <0.1 <0.1 12

 >10 13

  <1 14

  <1 15 15, Enantiomer 1 15, Enantiomer 2

  <1 <0.1   <1 16

17

18

19

  <1 20

 <10 21 21, Enantiomer 1 21, Enantiomer 2

<0.1   <1 <0.1 22

  <1 23 23, Enantiomer 1 23, Enantiomer 2

  <1   <1 <0.1 24

  <1 25, Enantiomer 2

  <1 26 26, Enantiomer 1 26, Enantiomer 2

<0.1   <1 <0.1 27 27, Enantiomer 1 27, Enantiomer 2

<0.1   <1 <0.1 28

<0.1 29, Enantiomer 2

<0.1 30, Enantiomer 2

<0.1 31, Enantiomer 2

<0.1 32, Enantiomer 2

 >10 33, Enantiomer 2

  <1 34, Enantiomer 1 34, Enantiomer 2

  <1   <1 35, Enantiomer 1 35, Enantiomer 2

<0.1 <0.1 36, Enantiomer 1 36, Enantiomer 2

 >10   <1 37, Enantiomer 1 37, Enantiomer 2

<0.1 <0.1 38 38, Enantiomer 1 38, Enantiomer 2

<0.1   <1 <0.1 39

  <1 40

 >10 41, Enantiomer 1 41, Enantiomer 2

  <1  <10 42, Enantiomer 1 42, Enantiomer 2

 <10 <0.1 43, Enantiomer 2

 <10 44, Enantiomer 2

 <10 45, Enantiomer 2

 <10 46, Enantiomer 2

 <10 47, Enantiomer 2

 >10 48

 >10 53

  <1 54

  <1 55

 <10 

1. A compound of the formula

where R₁ is selected from the group consisting of H, halogen, C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, perhaloalkyl, CN, N(R₆)₂, SR₆, CON(R₆)₂, NR₆COR₇, NR₆CO₂R₇, SO₂N(R₆)₂, NR₆SO₂R7, aryl, heteroaryl, C₁₋₁₀alkylaryl, and C₁₋₁₀alkylheteroaryl; R₂ is selected from the group consisting of halogen, C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, perhaloalkyl, CN, OR₆, N(R₆)₂, SR₆, OCOR₇, CON(R₆)₂, NR₆COR₇, NR₆CO₂R₇, SO₂N(R₆)₂, NR₆SO₂R₇, aryl, heteroaryl, C₁₋₁₀ alkylaryl, and C₁₋₁₀alkylheteroaryl; and R₂ may also be H when R₅ is C₁₋₁₀ alkyl or R₄ is H; R₃ is selected from the group consisting of H, halogen, C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, perhaloalkyl, CN, OR₆, N(R₆)₂, SR₆, OCOR₇, CON(R₆)₂, NR₆COR₇, NR₆CO₂R₇, SO₂N(R₆)₂, NR₆SO₂R₇, aryl, heteroaryl, C₁₋₁₀ alkylaryl, and C₁₋₁₀alkylheteroaryl; R₄ is selected from the group consisting of H, halogen, C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, perhaloalkyl, CN, N(R₆)₂, SR₆, CON(R₆)₂, NR₆COR₇, NR₆CO₂R₇, SO₂N(R₆)₂, NR₆SO₂R₇, aryl, heteroaryl, C₁₋₁₀ alkylaryl, and C₁₋₁₀alkylheteroaryl; R₅ is selected from the group consisting of H, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, perhaloalkyl, CN, OR₆, N(R₆)₂, SR₆, OCOR₇, CON(R₆)₂, NR₆COR₇, NR₆CO₂R₇, NR₆SO₂R₇, aryl, heteroaryl, C₁₋₁₀alkylaryl, and C₁₋₁₀ alkylheteroaryl; R_(5a) is H; R₆ is selected from the group consisting of H, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, perhaloalkyl, C₁₋₁₀ alkyl-O—C₁₋₁₀ alkyl, aryl, heteroaryl, C₁₋₁₀alkyl-0-aryl, C₁₋₁₀ alkyl-O-heteroaryl, C₁₋₁₀ alkylaryl, and C₁₋₁₀ alkylheteroaryl; and R₇ is selected from the group consisting of C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, perhaloalkyl, C₁₋₁₀alkyl-O—C₁₋₁₀ alkyl, aryl, heteroaryl, C₁₋₁₀alkyl-O-aryl, C₁₋₁₀alkyl-O-heteroaryl, C₁₋₁₀ alkylaryl, and C₁₋₁₀ alkylheteroaryl; provided that if R₁, R₂, R₅ and R_(5a) are H, then R₃ and/or R₄ must be H, or a pharmaceutically acceptable salt thereof.
 2. A compound as in claim 1 selected from the group consisting of 1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole; and 6-Chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.
 3. A pharmaceutical composition comprising at least one compound of claim 1 and a pharmaceutically acceptable carrier.
 4. A method of treating a disease, disorder and/or condition in a patient wherein modulation of a 5-HT_(2c) function is desired comprising administering an effective amount of at least one compound of claim 1 to a patient in need of such treatment. 